Systems and methods for delivering agents into targeted tissue of a living being

ABSTRACT

Delivery systems for accessing the targeted tissue within the living being and introduction of at least one agent at select locations into the tissues of the heart such as the myocardium and other select tissues. Where appropriate, portions of the system are steerable to properly orient the device. When tissue penetration is utilized, the device may include a feature to control the depth of penetration. removal. The system may utilize some form of mechanical action or application of energy (e.g. electrical, sonic, thermal, optical, pressurized fluid, radio frequency (RF), nuclear) in the process. The agent delivered to the tissue may include one or more of pharmaceuticals, biologically active agents, radiopaque materials, etc.

RELATED APPLICATION

This application is a Continuation of U.S. patent application Ser. No.09/368,410, filed on Aug. 5, 1999 now U.S. Pat. No. 6,709,427, entitledSystems And Methods For Delivering Agents Into Targeted Tissue Of ALiving Being which is assigned to the same assignee as this invention,and whose disclosure is incorporated by reference herein.

BACKGROUND OF THE INVENTION

This invention relates generally to medical systems and procedures andmore particularly to systems and procedures for delivering a flowabletreatment agent into targeted tissues, e.g., cardiac tissue, of a livingbeing.

Cardiovascular disease is the leading cause of death in the industrialworld today. During the disease process, atherosclerotic plaques developat various locations within the arterial system of those affected. Theseplaques restrict the flow of blood through the affected vessels. Ofparticular concern is when these plaques develop within the bloodvessels that feed the muscles and other tissues of the heart. In healthyhearts, cardiac blood perfusion results from the two coronary arterialvessels, the left and right coronary arteries that perfuse themyocardium from the epicardial surface inward towards the endocardium.The blood flows through the capillary system into the coronary veins andinto the right atrium via the coronary sinus. When atherosclerosisoccurs within the arteries of the heart it leads to myocardialinfarctions, or heart attacks, and ischemia due to reduced blood flow tothe heart tissues. Over the past few years numerous devices and methodshave been evaluated for treating cardiovascular disease, and fortreating the resulting detrimental effects that the disease has upon themyocardium and the other heart tissues. They are: traditional surgicalmethods (e.g. open heart surgery), minimally invasive surgery,traditional interventional cardiology (e.g. angioplasty, atherectomy,stents), and advanced interventional cardiology (e.g. catheter baseddrug delivery). Other recent advances in cardiovascular diseasetreatment involve transmyocardial revascularization (TMR), and growthfactor and gene delivery.

Traditional methods for treating cardiovascular disease utilize opensurgical procedures to access the heart and bypass blockages in thecoronary blood vessels. These procedures require an incision in the skinextending from the supra-sternal notch to the zyphoid process, thesawing of the sternum longitudinally in half, and the spreading of therib-cage to surgically expose the patient's heart. Based upon the degreeof coronary artery disease, a single, double, triple, or even greaternumber of vessels are bypassed. Each bypass is typically performed bycreating a separate conduit from the aorta to a stenosed coronary arteryat a location distal to the occluded site. In general, the conduits areeither synthetic or natural bypass grafts. Grafting with the internalthoracic (internal mammary) artery directly to the blocked coronary sitehas been particularly successful with superior long-term patencyresults. During conventional cardiac surgery, the heart is stopped usingcardioplegia solutions and the patient is put on cardiopulmonary bypass.The bypass procedure uses a heart-lung machine to maintain circulationthroughout the body during the surgical procedure. A state ofhypothermia may be induced in the heart tissue during the bypassprocedure to preserve the tissue from necrosis. Once the procedure iscomplete, the heart is resuscitated and the patient is removed frombypass.

There are great risks associated with these traditional surgicalprocedures such as significant pain, extended rehabilitation time andhigh risk of mortality for the patient. The procedure is time-consumingand costly to perform. Traditional cardiac surgery also requires thatthe patient have both adequate lung and kidney function in order totolerate the circulatory bypass associated with the procedure and anumber of patients which are medically unstable are thus not a candidatefor bypass surgery. As a result, over the past few years, minimallyinvasive techniques for performing bypass surgery have been developedand in some instances the need for cardiopulmonary bypass and extendedrecovery times are avoided. A number of companies, e.g., Heartport, Inc.of Redwood City, Calif. and Cardiothoracic Systems, Inc. of Cupertino,Calif., have developed devices that allow for cardiac surgicalprocedures that do not require a grossly invasive median sternotomy ortraditional cardiopulmonary bypass equipment. The procedures result in asignificant reduction in pain and rehabilitation time.

In addition, as an alternative to surgical methods, traditionalinterventional cardiology methods (e.g. angioplasty, atherectomy, andstents) non-surgical procedures, such as percutaneous transluminalcoronary angioplasty (PTCA), rotational atherectomy, and stenting havebeen successfully used to treat this disease in a less invasivenon-surgical fashion. In balloon angioplasty a long, thin catheterhaving a tiny inflatable balloon at its distal end is threaded throughthe cardiovascular system until the balloon is located at the locationof the narrowed blood vessel. The balloon is then inflated to separateand expand the obstructing plaque and expand the arterial wall, therebyrestoring or improving the flow of blood to the local and distaltissues. Rotational atherectomy utilizes a similarly long and thincatheter, but with a rotational cutting tip at its distal end forcutting through the occluding material. Stenting utilizes a balloontipped catheter to expand a small coil-spring-like scaffold at the siteof the blockage to hold the blood vessel open.

While many patients are successfully relieved of their symptoms and painwith traditional interventional procedures, in a significant number ofpatients the blood vessels eventually restenose or reocclude within arelatively short period of time. As such, researchers have exploredadvanced interventional cardiology methods (e.g., catheter based drugdelivery, radiation therapy, etc.) to delay or prohibit the process ofrestenosis. As summarized by Raoul Bonan, MD (“Local Drug Delivery forthe Treatment of Thrombus and Restenosis, IAGS Proceedings, The Journalof Invasive Cardiology, 8:399-408, October 1996), the cardiologycommunity has recently begun to augment standard catheter-basedtreatment techniques with devices that provide local delivery ofmedications to the treated site. This localized administration of drugshas shown promise for counteracting clotting, reducing inflammatoryresponses, and blocking proliferative responses.

Several devices are reported to be under evaluation for site specificdrug delivery, such as the so-called “Channel Balloon” catheter ofBoston Scientific (Natick, Mass.), the “Infiltrator” device ofInterVentional Technologies (San Diego, Calif.), the “InfusaSleeve”device of LocalMed Inc. (Sunnyvale, Calif.), the “Dispatch” catheter ofSciMed/Boston Scientific (Natick, Mass.), and an ultrasound enhancedcatheter of EKOS (Bothell Wash.). The “Channel Balloon” catheter is anover-the-wire catheter with separated ports for balloon inflation anddrug infusion. The “Infiltrator” device utilizes nipples in a balloon toforce a drug into vessel wall.

U.S. Pat. No. 5,279,565 (Klein et al.) discloses a device for infusing atreatment site with a medicinal agent. The device has a flexible bodyand deflectable support frames that are deployed radially against theintended treatment site. The InfusaSleeve device of LocalMed, Inc.slides over existing balloons to position drug delivery ports againstthe artery wall. The Dispatch is an over the wire catheter with separateports for drug infusion and balloon inflation.

U.S. Pat. No. 5,527,292 (Adams et al.) describes an intravascular devicehaving an elongated flexible tube sized for insertion into a coronaryvessel beyond a distal end of a guide catheter. In certain applications,the intravascular device is used as a drug (or other fluid) deliverydevice or as an aspiration device. In other applications, theintravascular device is used as a guiding means for placement of anangioplasty device, such as a guide wire or a balloon catheter. EKOS(Bothell, Wash.) has developed a site-specific catheter that usesultrasound energy to enhance the performance of a thrombolytic drug. Theultrasound energy transports the drug molecules into the strands offibrin bundles to dissolve clots more effectively than drugs alone.Several other drug delivery catheters have been described.

Balloon-tipped catheters, appropriate for drug delivery procedures, arealso described in U.S. Pat. No. 5,087,244 (Wolinsky et al.). Inparticular, this patent describes a catheter having a balloon near itsdistal end is expanded with a medication that then flows through minuteholes in the balloon surface at a low flow rate. The catheterpressurizes the medication so that it can be perfused at a controlledlow flow rate to penetrate into the wall of the localized tissue.

U.S. Pat. No. 5,021,044 (Sharkawy) describes an intravascular treatmentapparatus having a plurality of holes on the outer surface of thecatheter body through which a drug may be delivered to a site within avessel.

U.S. Pat. No. 5,112,305 (Barath et al.) describes a catheter fordelivery of therapeutic chemical agents to an interior wall of a vessel,the catheter having a balloon near its distal end with tubularextensions projecting from its outer surface. The catheter ispressurized with a drug, which causes the balloon to expand. The drugthen flows throughout the tubular extension into the vessel wall.

U.S. Pat. No. 4,406,656 (Hattler et al.) describes a collapsiblemulti-lumen venous catheter that can be used for drug injection.

U.S. Pat. No. 5,498,238 (Shapland et al.) discloses a method ofsimultaneous angioplasty and drug delivery to a localized portion ofcoronary or peripheral arteries or any other type of body passage thathas a stricture. The drug delivery device is first positioned in a bodypassageway. The device is expanded in order to dilate the passage whilesimultaneously causing a selected drug to be transported across a drugtransport wall of the device for direct contact with the passagewaywall.

U.S. Pat. No. 5,415,637 (Khosravi) describes an intravascular catheterthat is capable of delivering a drug, that is in the form of an alreadymixed solution or in the form of pellets, both intraluminally andendoluminally to an artery.

United States Letters Patent No. (Spears) describes a method fortreating a lesion in an artery by bonding a bioprotective material tothe arterial wall with thermal energy to provide localized drugdelivery. The device can use drugs that are trapped within microspheresthat can be thermally bonded to tissues.

U.S. Pat. No. 4,994,033 (Shockey et al.) describes an intravasculartreatment apparatus having a pair of expansion members concentricallyarranged near its distal end wherein a drug is delivered to the outerexpansion member. The expansion member expands against the vessel wallforcing the drug through minute holes in the outer member to bathe thevessel wall.

U.S. Pat. No. 5,456,667 (Ham et al.) describes an intravascular catheterwith an expandable region formed of a tubular material at the distal endof the catheter body in a one-piece configuration and is radiallyexpanded and contracted by means of a control wire. The interior of theexpandable region is in fluid communication with a lumen in the catheterbody to allow the delivery of a fluid to the artery via openings in thesurface of the expandable region. The catheter is particularly adaptedto hold open an artery after a vascular procedure such as a balloonangioplasty, and if desired to introduce a therapeutic drug or otherfluid to the site of the vascular procedure.

The assignee of this present invention is also the assignee ofpreviously described catheter-based devices for the local delivery ofdrugs into the arterial system. See for example, U.S. Pat. No. 4,589,412(Kensey) and U.S. Pat. No. 4,631,052 (Kensey) disclose atherectomycatheters that utilize a cutting tip that is driven by the applicationof fluid pressure. As described, the catheters can be used to deliverdrugs, oxygen, nitrates, calcium channel blockers or contrast mediathrough the catheter tip into the arterial lumen.

U.S. Pat. No. 4,747,406 (Nash) and U.S. Pat. No. 4,686,982 (Nash), whichare assigned to the same assignee as this invention, describerecanalization catheters with a high speed working end that is driven bya flexible drive shaft mounted within a bearing. The specificationdescribes the use of fluid to cool and lubricate the catheter, as wellas reduce the incidence of snagging as a result of the positive pressureapplied to the artery wall. The fluid can include nitrates, drugs, orcontrast media.

U.S. Pat. Nos. 4,664,112 (Kensey), 4,679,558 (Kensey et al.), and4,700,705 (Kensey), assigned to the same assignee as this invention,describe small diameter catheter devices with a high-speed working headused for dilating lumens and stopping arterial or other lumen spasm. Thespecifications describe the use of fluids to cool and lubricate thecatheter. The fluid can carry contrast media or drugs. The catheters maybe useful for opening restrictions in lumens by bombarding therestriction with propelled fluids at high pressure which may force theliquid into the lumen walls by increasing the local dynamic orhydrostatic pressure induced by the injected liquid or the movingworking head.

U.S. Pat. No. 4,790,813 (Kensey), also assigned to the same assignee asthis invention, describes an atherectomy catheter that utilizes acutting tip that is driven by the application of fluid pressure. Asdescribed, that catheter has the potential for the delivery of drugs,oxygen, nitrates, calcium channel blockers or contrast media through thecatheter tip into the arterial lumen.

U.S. Pat. No. 4,795,438 (Kensey et al.), also assigned to the sameassignee as this invention, describes a flexible small diameter catheterfor effecting the formation of a restriction in a vessel. The patentteaches of a rotary catheter that is used to deliver fluid, particles,sclerosing liquid, micron-sized particles, and adhesive agents. In oneaspect of the invention, the particles are embedded into the tissuecontiguous with the working head of the catheter. The embedded particlescause the tissue to change, e.g. form scar tissue, whereupon arestriction is formed. Another aspect of the invention describes the useof abrasive particles to sclerose or abrade tissue.

U.S. Pat. Nos. 4,749,376 (Kensey et al.), 5,042,984 (Kensey et al.), and4,747,821 (Kensey et al.), all assigned to the same assignee of thisinvention, describe drive-wire driven rotary catheters for opening anarterial restriction. The devices utilize the rotation of a working headto cause fluid to be thrown radially outward from the working head toimpact the artery wall.

In general, these previous devices are suited to deliver drugs and othertherapeutic agents locally to the immediate lumen (e.g., artery) wall toaddress restenosis. However, they do not address the problem of treatingother heart tissues (e.g., myocardium) located beyond the arterial wall.

It has been shown that some patients can receive significant benefitsfrom recently developed medical treatments. Some of these treatments areapplied to other tissues of the heart (e.g. the myocardium). Inaddition, although the non-surgical interventional cardiology proceduresare much less costly and less traumatic to the patient than traditionalcoronary bypass surgery, there are a number of patients for which theseprocedures are not suitable. For certain types of patients the presenceof extremely diffuse stenotic lesions and total occlusion in tortuousvessels prohibits them from being candidates for traditional cardiacsurgery. For these patients, direct myocardial revascularization hasbeen performed by inducing the creation of new channels, other than thecoronary arteries themselves, which are designed to supply oxygenatedblood and remove waste products from the heart tissue (e.g. myocardium).Myocardial revascularization is a technique that was conceived tosupplement the blood supply delivered to the heart by providing theischemic inner surface of the heart, known as the endocardium, withdirect access to the blood within the ventricular chamber. Typically theendocardium receives its nutrient blood supply entirely from thecoronary arteries that branch through the heart wall from the outersurface known as the epicardium.

Needle acupuncture approaches to direct myocardial revascularizationhave been made and were based upon the premise that the heart ofreptiles achieve myocardial perfusion via small channels between theleft ventricle and the coronary arterial tree as described by Sen et al.in their article entitled “Transmyocardial Acupuncture: A New ApproachTo Myocardial Revascularization” in the Journal of Thoracic andCardiovascular Surgery, 50:181-187, August, 1965. In that article it wasreported that researchers attempted to duplicate the reptilian anatomyto provide for better perfusion in human myocardium by perforatingportions of the ventricular myocardium with 1.2 mm diameter needles in20 locations per square centimeter. It has been shown that the perfusionchannels formed by mechanical methods such as acupuncture generallyclose within two or three months due to fibrosis and scaring. Pifarre etal. evaluated the feasibility of direct myocardial revascularizationfrom the left ventricle through artificially created channels. Theirresults are described in an article entitled “MyocardialRevascularization by Transmyocardial Acupuncture, A PhysiologicImpossibility” in the Journal of Thoracic and Cardiovascular Surgery,58:424-431, September, 1969. Pifarre et al. concluded that results werenot encouraging. As a result, these types of mechanical approaches wereabandoned in favor of other methods to effect the transmyocardialrevascularization (TMR).

Similar revascularization techniques have involved the use ofpolyethylene tubes, endocardial incisions, and the creation ofperforated or bored channels with various types of needles, and needleacupuncture. For example, T-shaped tubes have been implanted in themuscle, with the leg of the T-tube extending into the ventricular cavityas reported by Massimo et al. in an article entitled “MyocardialRevascularization by A New Method of Carrying Blood Directly From theLeft Ventricular Cavity into the Coronary Circulation” appearing in J.Thorac. Surg., 34:257-264, August, 1957. In an article entitled“Experimental Method For Producing A Collateral Circulation To The HeartDirectly From The Left Ventricle” by Goldman et al. in the Journal ofThoracic and Cardiovascular Surgery, 31:364-374, March 1965, severalexperimental methods for myocardial revascularization are described. Onemethod involved the implantation of excised perforated carotid arteriesinto the left ventricular wall. Goldman et al. also examined the use ofimplanted perforated polyethylene tubing in a similar fashion.

U.S. Pat. No. 5,591,159 (Taheri) describes a device for effectingmyocardial perfusion that utilizes slit needles to perforate themyocardium. The device uses a trans-femoral approach to position thedevice into the left ventricle of the patient. A plunger is activated tocause the needles to enter the myocardium several times. Perforation ofthe myocardium may be effected by means of a laser beam transmittedthrough the lumen of the needle or high velocity drill.

U.S. Pat. No. 5,655,548 (Nelson et al.) describes a method for perfusingthe myocardium using a conduit disposed between the left ventricle andthe coronary sinus. In one method, an opening is formed between the leftventricle and the coronary sinus, and the coronary ostium is partiallyoccluded using a stent that prevents the pressure in the coronary sinusfrom exceeding a predetermined value. Blood ejected from the leftventricle enters the coronary sinus during cardiac systole. Theapparatus limits the peak pressure in the coronary sinus to minimizeedema of the venous system. The system utilizes retroperfusion via thecoronary sinus of the venous system.

U.S. Pat. No. 5,755,682 (Knudson et al.) describes a device thatestablishes a channel leading directly from a chamber of a heart to acoronary artery. In one described method, a channel is created thatextends through the deep coronary arterial wall through underlyingcardiac musculature into the underlying chamber of the heart by using ascalpel, electro-surgical cutting blade, laser, or by radio-frequencyablation. A device is placed inside the channel to conduct blood fromthe heart chamber into the coronary artery.

Previous researchers had explored long term retroperfusion via thecoronary sinus but found that its leads to edema of the cardiac veinswhich are incapable of sustaining long-term pressures above about 60 mmHg. The procedure basically places a stent-like plug in the leftventricle so that blood flows into the coronary sinus and then into themyocardium via the venous system using retroperfusion, not into themyocardium directly. In the aforementioned Nelson et al. patent there isdisclosed the use of a cutting instrument, such as a cannulated needle,a rotating blade, or medical laser to provide the required opening forthe conduit. It is believed that when implanted in the heart, the plugand stent will result in long-term retrograde perfusion of themyocardium using the cardiac venous system and will cause aredistribution of the flow within the venous system so that a greaterfraction of the deoxygenated blood will exit through the lymphatic stemand the Thebesian veins (any of the minute veins of the heart wall thatdrain directly into the cavity of the heart). The inventors alsodescribe the use of a conduit that takes the place of the coronarysinus.

Researchers have also evaluated the used of lasers to create channels inthe myocardium. U.S. Pat. No. 4,658,817 (Hardy) describes a surgicalcarbon dioxide laser with a hollow needle mounted on the forward end ofthe hand-piece. The needle is used to perforate a portion of the tissue,for instance the epicardium, to provide the laser beam direct access todistal tissue of the endocardium for lasering and vaporization. Thedevice does not vaporize the tissue of the outer wall instead itseparates the tissue which recoils to its native position after theneedle's removal. This technique eliminates surface bleeding and theneed for suturing the epicardium as is done with other techniques. Thedevice includes a port that allows the needle to be cleaned via aninjection of saline.

In U.S. Pat. No. 5,607,421 (Jeevanandam) discloses that laser channelsremain open because carbonization associated with the laser energyinhibits lymphocyte, macrophage, and fibroblast migration. Thus, incontrast to channels created by needle acupuncture, laser channels healmore slowly and with less scar formation, which allowsendothelialization and long term patency.

An article entitled “New Concepts in Revascularization of Myocardium”(by Mirhoseini et al. in Ann. Thor. Surg., 45:415-420, April 1988)discusses the work of investigators exploring several differentapproaches fordirect revascularization of ischemic myocardium. Onerevascularization technique utilizes “myoepexy”, which consists ofroughening of the myocardial surface to enhance capillarization. Anothertechnique, known as “omentopexy” (the operation of suturing the omentumto another organ), consists of sewing the omentum over the heart toprovide a new blood supply. Another approach involves implanting theleft internal mammary artery directly into heart muscle so that bloodflowing through the side branches of the artery will perfuse the muscle.

It has been reported by Moosdorf et al. in their article entitled“Transmyocardial Laser Revascularization—Morphologic PathophysiologicAnd Historical Principles Of Indirect Revascularization Of The HeartMuscle” in Z Kardiol, 86(3): 147-164, March, 1997 that thetransmyocardial laser revascularization results in a relevant reductionof clinical symptoms such as angina and an increase of exercise capacityin approximately two thirds of the patients treated. Objective data ofenhanced myocardial perfusion as assessed by positron emissiontomography, thallium scans, and stress echocardiography has also beenpresented in other studies. Some researchers have found that TMRchannels created by CO2 lasers are surrounded by a zone of necrosis withan extent of about 500 microns. In heart patients who died in the earlypostoperative period (1 to 7 days) almost all channels were closed byfibrin clots, erythrocytes, and macrophages. At 150 days post procedure,they observed a string of cicatricial tissue (scar tissue resulting fromthe formation and contraction of fibrous tissue in a flesh wound)admixed with a polymorphous blood-filled capillary network and smallveins, which very rarely had continuous links to the left ventricularcavity. At the 2-week post procedure point a granular tissue with highmacrophage and monocyte activity was observable. See for example, thearticle by Krabatsch et al. entitled “Histological Findings AfterTransmyocardial Laser Revascularization” appearing in J. Card. Surg.11:326-331, 1996, and the article by Gassier et al. entitled“Transmyocardial Laser Revascularization. Historical Features In HumanNonresponder Myocardium” appearing in Circulation, 95(2): 371-375, Jan.21, 1997.

PLC MEDICAL's (Franklin, Mass.) Heart Laser and Eclipse's (Sunnyvale,Calif.) TMR 2000 laser revascularization system's have recently beenclinically tested and neither device has shown significant survivalbenefit between laser-based transmyocardial revascularization andmedical management. However, in general the use of the devices didresult in a two-class reduction in angina symptoms in the monthsfollowing the procedure. Recent data was reported with respect tofunctional improvement, long-term survival, and angina relief afterthree years in 70 patients suffering from refractory angina yet notamenable to conventional revascularization. The patients were treatedwith PLC's CO2 Heart Laser. After the revascularization procedure withthe Heart Laser, the angina class reduction seen at the first yearpersisted for at least three years with an accompanying increase inexercise tolerance. A significant increase in long-term mortality wasnot observed, however.

To date, studies have shown that no matterwhich laser, CO2 or Holmiumare used, the clinical results following a laser-based transmyocardialrevascularization procedure were almost identical: patients had anincrease in exercise tolerance, a two-class reduction in anginasymptoms, and no significant alteration in left ventricular ejection.BAXTER, J&J, CARDIODYNE and BARD/CORMEDICA are other companies that arealso exploring laser-based TMR systems.

In co-pending U.S. patent application Ser. No. 08/958,788, filed on Oct.29, 1999, entitled Transmyocardial Revascularization System, which isassigned to the same assignee as this invention and whose disclosure isincorporated by reference herein, there is disclosed a system making useof mechanically created punctures to provide the same benefits aslaser-created channels by initiating a healing response and effectingdenervation in the myocardium. In particular, that system makes use ofimplants within the myocardial tissue to perpetuate a foreign body orhealing response. That application additionally discloses the use ofpharmaceuticals, growth factors and genetic material to provide theheart with an initial and perpetuating stimulus for healing itself.

More recently, other researchers have had related ideas Pelletier et al.examined myocardial channels created by lasers and the resulting injurythat leads to an angiogenic response mediated by a number of growthfactors. This work is described by Pelletier in “Angiogenesis and GrowthFactor Expression in a Model of Transmyocardial Revascularization”(Annals of Thoracic Surgery, 66:12-18, 1998). With similar thoughts inmind, other companies are also investigating non-laser alternatives formyocardial revascularization. ANGIOTRAX (Sunnyvale, Calif.) isinvestigating a percutaneous device and flexible tip surgical handpiecefor mechanically creating channels. BOSTON SCIENTIFIC (Natick, Mass.) isworking with ARTHROCARE on the development of a radio-frequency (RF)system for percutaneous TMR. The device creates holes in the myocardiumwith needle electrodes that deliver RF energy at 450 kHz. The deviceutilizes a catheter that has been designed by SciMed. RADIUS MEDICAL(Maynard, Mass.) is exploring a percutaneous RF devices that utilizes ahollow guidewire, 0.021 or 0.035 inches in diameter that utilizes 13kHz, that is passed through a 6 French diagnostic catheter. Contrastmedia is injected through the hollow wire to help position the devicetip against the endocardial tissue. RADIUS believes that the hollow wirecan be used to infuse proteins or genetic material into the myocardium.U.S. Pat. No. 5,810,836 (Hussein et al.) describes a stent for insertioninto a heart wall for transmyocardial revascularization. The devicegenerates needle-made, or drilled, channels in the heart wall. A stentis implanted in each channel to maintain the patency of the channel. InEuropean Patent Application No. 97107784.7, assigned to United StatesSurgical of Norwalk, Conn., a coring device is described for removingtissue during a biopsy or transmyocardial procedures. The coring memberis rotatable and linearly advanceable at coordinated predetermined ratesto core body tissue. The tissue can be cauterized during the coringprocedure. European Patent Application number 98201480.5 and PCTInternational application number PCT/US98/08819 of C. R. BARD in MurrayHill, N.J. describes a “TMR stent and delivery system.” That systemincludes a device which pierces the myocardial tissue and a stent whichis implanted to permit the flow of blood from the left ventricledirectly into the tissue for direct revascularization. PatentCooperation Treaty (PTC) international application number PCT/US97/03523of Energy Life Systems of Costa Mesa, Calif. describes a similar system.German patent number DE 296 19 029 U1 (Kletke) describes a needle formyocardial penetration. A needle is used to create a series of puncturecanals. The canals are protected by the placement of continuous lengthof a resorbable suture, which is looped into each puncture.

In addition, researchers are exploring the percutaneous and directsurgical injection of growth factors and genetic material. Mack et al.describes experiments to improve myocardial perfusion in an articleentitled “Biologic Bypass with the Use of Adenovirus-Medicated GeneTransfer of the Complementary Deoxyribonucleic Acid for VascularEndothelial Growth Factor 121 Improves Myocardial Perfusion and Functionin the lschemic Porcine Heart” in The Journal of Thoracic andCardiovascular Surgery 115:168-177, January 1998. Sanborn et al.described the potential injection of angiogenic proteins and genesdirectly into the heart via the endocardium with a percutaneousfluoroscopically guided system in an abstract entitled “PercutaneousEndocardial Gene Therapy: In Vivo Gene Transfer and Expression” in theJournal of the American College of Cardiology 33:262A, February 1999.Uchida et al. described growth factor injections in “Angiogenic Therapyof Acute Myocardial Infarction by Intrapericardial Injection of BasicFibroblast Growth Factor and Heparin Sulfate: An Experimental Study”American Heart Journal 130:1182-1188, December 1995. Uchida utilized acatheter system for percutaneous transluminal administration of drugsthrough the right atrium into the pericardial cavity with a 23 gauge 4mm long needle. U.S. Pat. No. 5,244,460 (Unger et al.) describes amethod for inserting a catheter into a coronary artery and for infusingmultiple coronary drug injections, containing blood vessel growthpromoting peptides (i.e. fibroblast growth factor), through an infusionport into the catheter over a period of time.

In summary, there are a number of potential mechanisms whichindividually or in combination may be responsible for the improvementsseen in patients subjected to the previously described myocardialrevascularization techniques including: (1) new blood flow through thecreated channels, (2) angiogenesis (stimulation of the creation of newblood vessels), (3) cardiac denervation, (4) the placebo effect, (5)ablation of ischemic myocardium, and (6) formation of collateralcirculation.

Currently it is believed that cardiac denervation and angiogenesis arethe primary causes for post procedure angina relief and improvedperfusion respectively. The injury damages nerves thereby minimizing thepain sensation and stimulates angiogenesis. While the aforementionedtechniques and methods for revascularizing the myocardium offer somepromise they never the less suffer from one disadvantage or another. Asa first example, the lasers are very expensive to purchase. Theaforementioned U.S. patent application Ser. No. 08/958,788, filed onOct. 29, 1997 is directed to the same or similar medical benefitsachieved by use of non-laser devices, such as those disclosed andclaimed therein. As a second example, the design of the interventionalcardiology catheter-based drug delivery systems appear unable todelivery drugs to tissues located beyond the arterial walls. Significantbenefit could be gained by the delivery of agents (e.g. foreign bodyparticles, drugs, growth factors, genetic material, etc.) into hearttissues beyond the arterial wall. Those devices that have considereddirect injection of drugs or genetic material into the myocardium simplydeposit the material within a channel that is typically created by aneedle. As the myocardium dynamically contracts, deposits of materialsin these channels will likely migrate unless stabilized with amechanical or chemical anchor of some sort. It is the intent of thisinvention to overcome these and other shortcomings of the prior art.

OBJECTS OF THE INVENTION

Accordingly, it is a general object of this invention to provide asystem and methods for treating targeted internal tissue, e.g., cardiactissue or other internal tissue, of a living being which overcomes theshortcomings of the prior art.

It is a further object of this invention to provide a system and methodfor myocardial revascularization that overcomes the disadvantages of theprior art.

It is a further object of this invention to provide a system and methodfor vascularizing the cardiac tissue of a living being to cause theformation of lumens in communication with the being's arterial system.

It is a further object of this invention to provide a system and methodfor treating cardiac tissue of a living being to affect the conductionof electrical signals in the cardiac tissue.

It is a further object of this invention to provide a system and methodfor treating cardiac tissue of a living being to affect the conductionof nerve signals in the cardiac tissue.

It is a further object of this invention to provide a system and methodsfor treating targeted internal tissue, e.g., cardiac tissue or otherinternal tissue, by delivering flowable agent(s) thereto.

It is a further object of this invention to provide a system andmethodology for providing relief from myocardial ischemia.

It is a further object of the present invention to provide a systemhaving delivery capabilities delivering agents flowable agents tointernal body tissues for beneficial purposes, such as, but not limitedto treating heart disease.

It is a further object of this invention to provide apparatus andmethods for providing myocardial perfusion that reduce the level ofischemia in a living being.

It is a further object of this invention to provide methods andapparatus for reducing the level of discomfort associated with angina ina living being.

It is a further object of this invention to provide apparatus andmethods to enable living beings that suffer from the later stages ofischemic heart disease to experience reduced pain and improved emotionalwell being.

It is a further object of this invention to provide a transmyocardialrevascularization system and methodology that is simple and costeffective.

It is a further object of this invention to provide an apparatus andmethod for myocardial revascularization to increase blood flow to themyocardium from the endocardium without using the native diseasedcoronary arteries.

It is a further object of this invention to provide an apparatus andmethod for myocardial revascularization to be used with living beingshaving extensive coronary atherosclerosis.

It is a further object of this invention is to provide apparatus andmethods for effecting endovascular myocardial revascularization.

It is a further object of the present invention to provide methods andapparatus which can be utilized either in open surgical, minimallyinvasive surgical, or transluminal techniques to deliver beneficialagents to the myocardium.

It is a further object of this invention to provide a system and methodfor direct myocardial revascularization without the need for opening thechest cavity.

It is a further object of this invention to provide as system and methodfor direct endovascular myocardial revascularization without having toutilize a laser, although a laser may be used, if desired, in someapplications as part of the procedure.

It is a further object of this invention to provide a system and methodto create channels in the myocardium without having to utilize a laser,although a laser may be used, if desired, in some applications as partof the procedure.

It is a further object of this invention to provide a system and methodfor effecting initial and prolonged stimulus within the myocardium thatinstigates the heart to heal itself.

It is a further object of this invention to provide instruments withdelivery capabilities for dispersing flowable agent(s) into targetedinternal tissues of a living being at a location beyond that which isimmediately adjacent the instrument.

SUMMARY OF THE INVENTION

These and other objects of this invention are achieved by providingtissue, e.g., cardiac, treatment systems and methods of treating tissue,such as the myocardium and other tissues, within the body of a livingbeing.

The treatment system can be used for vascularizing the cardiac tissue ofa living being to cause the formation of lumens in communication withthe being's arterial system, or can be used to affect the conduction ofelectrical signals in the cardiac tissue, or can be used to affect theconduction of nerve signals in the cardiac tissue, or in some waybeneficially treat other (e.g., non-cardiac) tissue within the body ofthe being.

To that end the treatment system comprises a delivery instrument and aflowable agent. The flowable agent comprises a plurality of smallparticles for introduction into the cardiac tissue or other tissue. Thedelivery instrument is arranged to introduce the flowable agent at oradjacent the cardiac or other targeted tissue by imparting a force tothe agent, whereupon the agent directly enters the cardiac or othertargeted tissue at an entry situs.

DESCRIPTION OF THE DRAWINGS

Other objects and many attendant features of this invention will becomereadily appreciated as the same becomes better understood by referenceto the following detailed description when considered in connection withthe accompanying drawing wherein:

FIG. 1A is an illustration of the heart of a living human being,partially in section, showing one embodiment of a delivery instrumentforming a portion of the tissue treatment, e.g., myocardialrevascularization, system of the subject invention being used topenetrate a portion of the septum to deliver flowable agent(s) to thetargeted tissue, e.g., the septum, via the endocardium;

FIG. 1B is an illustration similar to that of FIG. 1A, but showing theembodiment of the delivery instrument being used to penetrate a portionof the myocardium to deliver the flowable agent(s) into the myocardiumvia the endocardium;

FIG. 2 is an enlarged sectional view of the distal portion of thedelivery instrument embodiment illustrated in FIGS. 1A and 1B, andshowing the flow paths of the agent(s) through and out of the instrumentfor dispersion into the targeted tissue;

FIG. 3A is an enlarged side sectional view of one embodiment of arupturable capsule containing a dose of the flowable agent(s) fordelivery into the targeted tissue by various delivery instruments of thesubject invention;

FIG. 3B is an enlarged side sectional view of one embodiment of apiercable capsule containing a dose of the flowable agent(s) fordelivery into the targeted tissue by various delivery instruments of thesubject invention;

FIG. 4A is an enlarged side elevational view, partially in section, ofthe embodiment of the needle access capsule of FIG. 3B, positionedwithin a capsule injector forming a portion of the delivery instrumentof FIG. 1;

FIG. 4B is an enlarged side elevational view, partially in section, ofthe embodiment of the rupturable capsule of FIG. 3A, positioned within acapsule injector forming a portion of the delivery system of FIG. 1;

FIG. 5A is a schematic diagram and system illustration showing oneembodiment of an entire targeted tissue treatment system making use ofthe delivery instrument of FIG. 1 for delivering the flowable agent(s)into a portion of the myocardium in accordance with the vascularizationtechnique illustrated in FIG. 1B;

FIG. 5B is a schematic diagram and system illustration similar to thatof FIG. 5A, but showing an embodiment of the entire targeted tissuesystem making use of the delivery instrument of FIG. 1 for deliveringthe flowable agent(s) into a portion of the myocardium via a coronaryartery to thereby effect myocardial vascularization;

FIG. 6 is an enlarged illustration of the heart of a living human being,partially in section, showing a portion of the delivery instrument ofFIG. 5B being used to deliver the flowable agent(s) into the myocardiumvia a coronary artery;

FIG. 7 is a side sectional view of one embodiment of an alternative,e.g., a rigid, delivery instrument of the targeted tissue treatmentsystem of this invention shown being used for effecting myocardialrevascularization by piercing the epicardium to create a channel in themyocardium, and deliver the flowable agent(s) therein by pressurizingthe agent(s);

FIG. 8 is a side sectional view of one embodiment of anotheralternative, e.g., a flexible, delivery instrument of the targetedtissue treatment system of this invention shown being used for effectingmyocardial revascularization by delivering the flowable agent(s)intravascularly through a vessel, e.g., coronary artery, wall intomyocardium;

FIG. 9 is an illustration of the heart of a living human being,partially in section, showing another alternative embodiment, e.g., avibratory, delivery instrument of the targeted tissue treatment systemof this invention shown being used to penetrate a portion of theepicardium and myocardium to deliver the flowable agent(s) into themyocardium;

FIG. 10 is an enlarged side sectional view showing a portion of thevibratory delivery instrument embodiment of FIG. 9 for penetratingtissue and delivering the flowable agent(s) into the myocardium;

FIG. 11 is a schematic diagram and system illustration showing anotherembodiment of a targeted tissue treatment system of this inventionincluding the embodiment of the vibratory delivery instrumentillustrated in FIG. 9 being used to penetrate and deliver the flowableagent(s) to a portion of the myocardium via the epicardium;

FIG. 12 is an illustration of the heart of a living human being,partially in section, showing one embodiment of an alternative deliveryinstrument forming a portion of the myocardial revascularization systemof the subject invention being used to deliver the flowable agent(s)into the myocardium via the epicardium;

FIG. 13 is a side sectional view of the embodiment of the deliveryinstrument of FIG. 7 with a stabilizing device, e.g., a suction hood,associated with it and shown being used to pierce the epicardium tocreate a channel in the myocardium and to deliver the flowable agent(s)into the channel in the myocardium;

FIG. 14 is a side sectional view of an embodiment of a deliveryinstrument, e.g., a flexible pressurized intravascular access deliveryinstrument, forming a portion of the tissue treatment system of thesubject invention being used delivery agents through the urethra wallinto the prostrate gland of a living being.

FIGS. 15A-15I are embodiments various exemplary types of particulatematerials which may make up all or a portion of the flowable agent(s) ofthe subject invention, in this case the materials being in the form ofmicrospheres and/or microparticles or other small particulates;

FIG. 16 is a side sectional view of one embodiment of a deliveryinstrument of a targeted tissue treatment, e.g., a myocardialrevascularization, system of this invention being used to pierce theepicardium, create a channel in the myocardium, and deliver the flowableagent(s) into myocardium whose vasculature has been reduced over time byatherosclerosis;

FIG. 17 is an illustration, like that of FIG. 16, but showing themyocardium immediately after the introduction of the small particles ofthe flowable agent(s) into the channel in the myocardium followed by theplacement of an insert into the channel to increase the vasculature ofby the myocardium by the creation of new vessels, e.g., capillaries, inthe myocardium;

FIG. 18 is an illustration like that of 17, but showing the myocardiumsome time after treatment by the system of FIGS. 16 and 17 where thedeployed particles and insert have stimulated angiogenesis to improvethe blood flow in the contiguous portion of myocardium;

FIG. 19 is an illustration of a portion of the heart of a living being,shown partially in section, and showing a flowable treatment agentdelivery system like that of FIG. 7 delivering the agent(s) at plurallocations to result in the production of an intramyocardial channel forproviding an enhanced blood supply to ischemic myocardial tissue;

FIG. 20 is an illustration of the portion of the heart shown in FIG. 19after the treatment procedure as depicted therein;

FIG. 21 is an enlarged sectional view of the distal or working end ofyet another alternative delivery instrument of the targeted tissuetreatment system of this invention; and

FIG. 22 is an enlarged sectional view of the distal or working end ofstill another alternative delivery instrument of the targeted tissuetreatment system of this invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Referring now to the drawing wherein like reference characters refer tolike parts, there is shown in FIG. 1A the distal portion of a deliverysubsystem 22 which will be described later and which forms a portion ofa tissue treatment, e.g., revascularization system, 20 constructed inaccordance with this invention.

These and other objects of this invention are achieved by providingtissue, e.g., cardiac tissue, treatment systems and methods of treatingtissue, such as the myocardium and other tissues within the body. Thesystems basically comprise a delivery system for accessing a targetedtissue within the living being and a flowable agent (to be described inconsiderable detail later) arranged to be introduced into the targetedtissue by the delivery system.

In several preferred embodiments shown and described herein the tissuetreatment system introduces the flowable agent into select portions ofthe myocardium, or other cardiac tissue.

As will be described later one or more of the delivery systems of thisinvention can be utilized during transluminal, transthoracic and directsurgical access procedures. Where appropriate, for example in the caseof intraventricular access, portions of the delivery system aresteerable to properly orient the delivery instrument. In someembodiments the delivery instruments are arranged to pierce the hearttissue and create channels extending from the endocardium, theepicardium, or the cardiac vessels. When tissue penetration is utilized,the delivery instrument can include a feature to control the depth ofpenetration. To minimize bleeding through the channels the deliveryinstrument can dilate small initial punctures that later contract downafter device removal. When the formation of channels is required, thiscan be achieved, by way of example, with a rotary-tipped device,pressurized fluid jet devices, vibratory instruments and piercingneedle-like tip devices.

The tissue treatment systems of this invention may utilize some form ofmechanical action or application of energy, e.g., electrical, sonic,thermal, optical (e.g., laser), pressurized fluid, radio frequency (RF),nuclear, in the process. The mechanical action or energy application mayaffect the surroundings tissues at a distance from the delivery system.For example, thermal energy may be conducted away via nerve conduitsthereby disabling the nerves and creating a condition of denervation. Asanother example, shockwaves created by sonic energy may travel throughthe tissue and serve to initiate a change that is beneficial to thepatient either immediately or over time.

The delivery instruments may make use of a device to stabilize a portionof the system or anatomy during the procedure (e.g., a vacuum stabilizeror surgical stabilizer ring). A controller may also be provided as partof the system to coordinate the operation of the delivery instrumentwith the cardiac cycle. For example, power to the delivery instrumentcan be synchronized with EKG leads, such that delivery instrumentoperation occurs at a recurring portion of the cardiac cycle.

Radiopaque contrast media, fluoroscopy, ultrasound, magnetic resonance,GPS-like triangulation, RF triangulation, flashback or otherimaging/position systems can be used to orient/position the deliveryinstrument during the procedure. Robotics could also be used to positionthe delivery instrument of the system in a body cavity or lumen. Forexample, a robotic arm can be used to navigate within the chest cavitythrough a small thoracic incision to position the delivery instrument inrelation to the epicardium.

In some applications, the delivery instrument is arranged to directlydeliver the flowable agent(s) into the cardiac tissue. In otherapplications a pressurized system imparts kinetic energy to the flowableagent(s) for the purpose of dispersing the agents into the tissuelocated beyond the tissue immediately adjacent the delivery instrumentof the system. Control parameters on the delivery instrument (e.g. apressure limiter) can provide control over agent penetration depth.

In some applications the dispersal pattern for the flowable agent(s) canbe selected and adjusted to provide for an optimum dispersion of theagent into the targeted tissue.

In applications, the pressurized system of the delivery instrumentdelivers the agents from the coronary vessels, the endocardium or theepicardium into the myocardium without the need to pierce the tissues ofthe artery, endocardium or epicardium. The delivery instrument can use agas, fluid, gel, or other suitable carrier to transport the flowableagent through the instrument and into contact with the tissue.

Although the preferred embodiment of the system will allow delivery ofthe agents into distant tissues, it may be beneficial to deposit some ofthe agents within an instrument created channel or to deliver a portionof the agent systemically via the circulatory system. Agents canpre-dosed in per-use packages or the system can draw doses ofpre-selected volumes from a reservoir. The system can vary theconcentration of the agent in a fluid, or other suitable carrier.

In accordance with some preferred embodiments of this invention theflowable agents are formed of at least one material that can elicit abeneficial response within the tissues. For example, at least a portionof the agents can be comprised of such items as a pharmaceutical, agrowth factor, a suitable biomaterial, or a genetic or cellular basedmaterial. The presence of the agent can initiate abio-chemical/biological process that stimulates the tissue to healitself. The agents can also trigger the onset of a foreign body orhealing response to cause the formation of lumens in communication withthe arterial system.

The flowable agents can be designed to assist the tissue in functioningmore effectively. For example, the agents could contain an electricallyconductive element that modifies or improves the contractile motion ofthe myocardium. It is contemplated that the mere presence of even aninert agent in the tissue may also be beneficial to a living being.Thus, for example, one embodiment of the invention described herein canbe used to deliver a select agent from within the urethra through theurethra wall and into the sphincter muscle to bulk up the sphincter as aremedy for urinary incontinence. As another example the system could beused to overcome the difficulty of transporting pharmaceuticals acrossthe blood-brain by providing positioning a portion of the system in thevicinity of the targeted tissue (e.g., brain tumor) and deliveringbeneficial agents. As yet another example, the system of the subjectinvention could be used to disperse beneficial agents (e.g. gene-basedelements) into the musculature of a patients with degenerative musclediseases (e.g., muscular dystrophy).

The flowable agents may be totally resorbable, partially resorbable ornon-resorbable. As an example they can be made of polymers, metals,elastomers, glass, ceramics, collagen, proteins or other suitablematerials or a combination materials. A collection of agents withvarying characteristics (e.g. density) can be delivered to the tissue toallow for a graduated deposition of varying types of agents to differentdepths of the tissue. Other agent characteristics (e.g. texture andabrasiveness) can be controlled to allow for varying degrees of traumato encountered tissues. Where the agents incorporate a solid component,the shape of the component can be varied from spheres to fibers to anyother desired shape. A form of a microsphere may be utilized to treatthe desired tissue region either by occupying space or by stimulating abiological response to the presence of them material or the release fromthe material of some chemical or biological element.

In the treatment of cardiac tissue, the presence of the flowable agentsof this invention when deployed in the myocardium will not appreciablyrestrict the cardiac contraction of the heart.

The flowable agents may be constructed to effect a time-phased deliveryof active ingredients. In summary, both the creation of channels and thedispersion of the agents is designed lead to improvements in patientswith cardiovascular disease as a result of: (1) angiogenesis(stimulation of the creation of new blood vessels), (2) cardiacdenervation (3) ablation of ischemic myocardium, and (4) formation ofcollateral circulation.

Turning now to FIG. 1A, there is shown a portion of a cardiacvascularization system 20 in the process of revascularizing themyocardium of a living, e.g., human, being. The entire system 20 isshown in detail in FIG. 5A and will be described in detail later.Suffice it for now to state that the treatment system 20 includesvarious components and subsystems which cooperate to effect the deliveryof flowable agents into relevant tissue of the being, e.g., the heart,the vascular system, etc. FIG. 1A is an illustration, not to scale, of asection of a healthy, human heart 1. As can be seen, the heart includesthe epicardium 2, the myocardium 3, the endocardium 4, the leftventricle 5, the right ventricle 6, the ventricle septum 7, the aorticvalve 8, the mitral valve 9, and the aorta 10. As can be seen clearly inFIG. 1A, the distal portion of the delivery subsystem 22 of system 20 isshown penetrating the ventricle septum and delivering the flowableagent(s) 24, which are denoted by the arrows in that illustration, intothe adjacent tissues of the septum. The subsystem 22 includes a deliveryinstrument 26 and a conventional, e.g., Judkins, guiding catheter orinstrument 28. The delivery instrument 26 of this embodiment basicallycomprises an elongated catheter having a high-speed, rotary working head30 located at the distal end thereof. The guiding instrument 28, whichwill be described later, is positioned to guide the delivery instrument26 to the desired location at the ventricle septum. The high speedworking head 30 of the delivery instrument is arranged to propel anddisperse the flowable agent into the adjacent tissue. The flowable agentmay be any type of flowable material, e.g., a fluid that alone or incombination with other additives such as drugs, growth factors,biocompatible microparticles, etc., is to be introduced into therelevant tissue for a desired purpose. The details of various of theflowable agents will be described later. When the delivery instrument 26is operated, its working head, e.g., the rotary working head of theembodiment described heretofore, or other types of working heads, ejectsor bombards the surrounding tissue with the propelled flowable agent(s)24 at high pressure to force the agent(s) into the tissue by increasingthe local dynamic or hydrostatic pressure induced by the agent or therotating working head. The construction of the delivery instrument 26allows the agent(s) 24 to be delivered and dispersed into a significantvolume of cardiac tissue.

It is important to note at this juncture that most prior art systems fordelivering medications to the heart do so either systemically by vein orregionally, e.g., intracoronary infusion. Systemic delivery is notefficient for the treatment of locally isolated disease for variousreasons, namely:

a wide range and large number of sites are exposed to the material,large quantities of the agent are required, due to the entire volume ofdistribution, to obtain the desired effect, and the agent degrades andcan be eliminated by various organ systems that keep the agent fromreaching the target site, thereby reducing the agent residence time inthe body.

As utilized in this invention, local intra-tissue delivery of theflowable agent(s) 24 eliminates these problems. In particular, theflowable agent(s) is (are) distributed into the target tissue and notjust deposited into the channel or puncture created in the tissue. Thenature of the pressurized flowable agent carries it to intra-cellularsites beyond the site of the initial puncture.

As will be appreciated by those skilled in the art, penetration into thetarget tissue is a function of the mass, density and speed of theagent(s). The agent(s) is (are) less likely to migrate away from thesite of implantation. When the treatment of the site is complete, thedelivery instrument 24 can be repositioned and the procedure repeated toimpregnate a new treatment site with the selected agent(s).

It is believed that the systems of the subject invention may be used assole therapy for end-stage heart disease patients that are not amenableto alternative therapies, such as coronary artery bypass surgery, or thesystems could be used as an adjunctive therapy in addition to othercardiac therapies such as PTCA, stenting, or coronary artery bypasssurgery.

FIG. 1B illustrates a portion of a transmyocardial revascularizationsystem 20 like that shown in FIG. 1A and constructed in accordance withthis invention and shown in the process of revascularizing themyocardium 3. In this illustration, the guiding instrument 28 ispositioned to guide the delivery instrument 26 toward the desiredlocation on the myocardium adjacent the left ventricle. The distalportion of the delivery instrument 26 is shown penetrating themyocardium and delivering the agent(s) 24, which are also denoted by thearrows, into the adjacent tissue of the myocardium.

FIG. 2 is an enlarged sectional view of the distal end portion of thedelivery instrument 26 which is illustrated in FIGS. 1A and 1B, andshowing the tissue penetrating system, utilizing the flow path of theagent(s) 24 through and out of the instrument. In accordance with onepreferred embodiment of this invention, the instrument is constructed ina fashion similar to those described in U.S. Pat. No. 4,747,821 which isassigned to the same assignee as this invention and whose disclosure isincorporated by reference herein. To that end, the working head 30 is arotary member which is arranged to revolve at a high speed in a bush 32driven by a double helical drive wire 34 from a remote,proximally-located motor or turbine (not shown). The bush 32 is mountedon the distal end of a flexible or rigid catheter jacket 36. Theagent(s) 24, under distribution, is delivered to the proximal end of thedelivery instrument 26 (not shown) and is transported down a centralpassageway therethrough alongside and between the helical drive wires 34to the bush 32, where the agent(s) 24 passes out of plural grooves 38provided in the center and end of the front portion of the bush,whereupon the agent(s) is further energized as it is centrifuged by therotation of the working head. The working head is arranged to revolveover a conventional guide wire 40, if one is needed for the procedure.The bush 32 is held in place at the distal end of the jacket by aretention band 42. A liner sleeve 44 extends down the center of thedouble helical drive wires 34. The distal end of the drive wires arefixedly secured, e.g., welded to a central shaft 46 of the working head30. The distal end of the working head is a generally dome-shaped cammember having flatted or relieved surfaces 48.

FIGS. 4A and 4B show two examples of delivery injectors forming aportion of the system 20 for propelling the flowable agent(s) 24 intoany of the delivery instruments of this system, such as the deliveryinstrument 26 described heretofore. In particular, FIG. 4A shows adevice 50 for propelling the agent(s) 24 from a rupturable, capsule 52.The injector 50 basically comprises a base plate 54 on which are mounteda capsule receiver 56 and a jack assembly 58. A needle 60 and associatedtubing 62 forming a subassembly are mounted in the receiver 56. Thetubing 62 is connected to a “highest wins valve” (to be described later)forming a portion of the system 20 for providing the flowable agent(s)to the delivery instrument 26 at the proximal end thereof. Another tubeor conduit (also to be described later) is in fluid communication withthe highest wins valve and the interior of the delivery instrument 26 sothat the flowable agent(s) which will be provided through the tubing 62enters into the instrument 26 flows therealong, as described above, andexits out of the instrument at the working head.

An enlarged view of the capsule 52 is shown in FIG. 3A. Thus, as can beseen therein, the capsule 52 comprises a container 62, made of a plasticsuch as polypropylene, and has a piston 64 at its proximal end. Thepiston 64 is made from a rubber compound similar to that used in medicalsyringes, and fits firmly, but slidably, in the container 64. On thedistal end of the container 64 is a rubber coating 66 which seals theagent(s) 24 within the capsule 52. The coating may also be located alongthe walls of the container 62, such as shown in FIG. 3A.

Referring again to FIG. 4A, it can be seen that in use the capsule 52 isplaced into a recess within the receiver 56 of the delivery injector andthe piston 64 is driven toward the distal end of the capsule by a ram 68of the jack assembly 58. This causes a sharp piercing end portion of theneedle 60 in the delivery device 26 to pierce the rubber 66 whereuponthe flowable agent(s) 24 flows into the delivery device 26 via thetubing 62 at a pressure determined by the rate of travel of the ram 68and the impedance of the distal located passageways, e.g., the tubing62, the passageway through the instrument 26, and the outlet deliveryports (e.g., the grooves 38 at the working head 30—see FIG. 2).

FIG. 4B shows a similar injector device 70 for propelling the agent(s)24 from the capsule 72. The injector 70 is virtually the same as theinjector 50, except that it doesn't include a needle 60. Thus, as can beseen, the injector 70 basically comprises a base plate 54 on which aremounted the capsule receiver 56 and the jack assembly 58. A tubingassembly 56 including tubing 62 is mounted on the receiver 56.

An enlarged view of the capsule 72 is shown in FIG. 3B. Thus, as can beseen, that capsule comprises a container 62, made of plastic such aspolypropylene, having a piston 64 at its proximal end. The piston ismade from a rubber compound similar to that used in medical syringes andfits firmly, but slidably, in the container 62. On the distal end of thecontainer is bonded a thin, frangible disk 74. The disk 74 is formed ofaluminum foil or a similar material and is coated with a plastic, suchas polyethylene, on its agent-contacting side (the inside). The diskserves to seal the agent(s) 24 within the capsule 62. The coating on thedisk also acts as a hot-seal medium when bonding the disk to thecontainer.

Referring again to FIG. 4B, in use the capsule 72 is placed into arecess within the receiver 56 and the piston 64 is driven toward thedistal end of the capsule 72 by the ram 64 of the jack assembly 58. Asthe pressure of the agent(s) 24 rises, the disk 74 ruptures and theagent flows through the associated port into the tubing 62 and theassociated instrument 26 at a pressure determined by the rate of travelof the ram and the impedance of the distal tubing and delivery ports,like that described earlier.

FIG. 5A is a schematic diagram and system illustration showing oneembodiment of the entire system 20. That system includes not only theguide instrument 28 and the delivery instrument 26 but also means tocontrol the operation of the delivery instrument in accordance with thesubject invention. The illustration of FIG. 1B shows only a portion ofthe system 20 used to penetrate and deliver agent(s) 24 to a portion ofthe myocardium via the endocardium, whereas the illustration of FIG. 5Ashows the entire system for achieving that end.

As mentioned, the delivery instrument 26 is a rotary device, whosedistal end is shown in detail in FIG. 2. The device 26 is arranged topass through the conventional guide catheter 28, which in thisapplication is preferably a steerable, guide catheter. That catheter hasa “J” shaped distal end and a knob 80 at the proximal end which used tosteer the “J” shaped distal end as shown in FIG. 5A. The details of thesteering mechanism are not shown in the drawing nor will be describedhereinafter, but may comprise any suitable means for achieving suchsteering action, such as that disclosed in U.S. Pat. No. 5,674,197 (vanMuniden et. al.), whose disclosure is incorporated by reference herein.The “J” shape of the distal end of the guide catheter 28 permits theuser to advance the delivery instrument 26 to the desired positionagainst the endocardium and by rotation of the guide catheter about itslongitudinal axis via the knob 80, the “J” shaped distal end can bedirected to any area of the ventricle 5.

The rotary working head 30 of the instrument 26 is driven by the drivecable from a turbine 82, via compressed nitrogen provided through a line84. The line 84 is coupled to a controller 86, whose construction andoperation will be described later, which receives compressed nitrogenfrom a tank or other source (not shown). The turbine 82 is mounted in acradle 88. The turbine 82 includes an output shaft which is connectedvia any suitable means (not shown) to the proximal end of the drivehelices 34. The turbine 82 is connected to the proximal end portion 90of the jacket 36 of the instrument 26 so that longitudinal movement ofthe turbine causes concomitant movement of the instrument 26. To thatend, the turbine 82 is slidably mounted in the cradle 88 in a mannerwhich permits the user to feed the delivery instrument 26 down the guidecatheter 28 to the precise location by moving a knob 94 connected to theturbine to and fro in a longitudinally extending slot 96 in the cradle88.

The steerable guide catheter 28 is coupled at its proximal end to adistal manifold 98, which in turn is connected via line 100 to aconventional angiographic manifold 102. The distal end portion of theinstrument 26 extends through a conventional hemostasis valve 104 toprevent the egress of blood from the interior of the guide catheter.

The angiographic manifold 102 is a conventional device such as thatcommonly used in laboratories and thus will not be described in detail.It will suffice to say that the physician uses the manifold 102 to passa contrast medium via the guide catheter 28 to the site of the deliveryinstrument's distal or working head 30 in the ventricle for assessmentof the location of the guide catheter and the delivery instrument byfluoroscopy.

The flowable agent(s) 24 to be delivered by the delivery instrument 26is provided in the capsule 62. The capsule is in turn mounted in theinjector 50. The agent delivery tube 62 is connected to one input 106Aof a conventional “highest wins” valve 106. The outlet from the valve106 is connected via a line 108 into a port in communication with theinterior passageway extending longitudinally through the jacket of thedelivery instrument 26. The other input 106B to the valve 106 isprovided via a line 110 from a peristaltic pump 112.

The controller 86 is an electrically powered device which is arranged toaccept inputs from a two-position foot control switch 114 to drive theperistaltic pump. The peristaltic pump is connected via a line to a bagor supply of saline 116. The electrically powered controller 86 isarranged to provide power via line 118 to the ram 58 of the injector 50.In addition, as noted earlier, the controller 86 provides the compressednitrogen via line 84 to the turbine 82 of the delivery instrument.

In use, the guide catheter 28 is extended from the patient entry situs,e.g., the femoral artery, through the vascular system under fluoroscopevision until its distal end is in the appropriate location within theventricle. The delivery instrument 26 is then advanced through the guidecatheter until its working head 30 at its distal end is adjacent theventricular wall. The foot control switch 114 is then depressed by theoperator to a first switch position to cause the turbine 82 of thedelivery instrument to operate, whereupon saline from the bag 116 isdelivered to the instrument. In particular, the saline is pumped by pump112 into communicating line 110, through the input line 106B of thehighest wins valve 106 and its communicating outlet line 108 into theinterior passageway of the delivery instrument. From there it flowslongitudinally down the central passageway whereupon it exits from thedistal end or at the working head. The operation of the turbine effectsthe concomitant high speed rotation of the working head. The operatorthen grasps the slide knob 94 on the cradle 88 and pushes it forwardwhile the working head is rotated at the high speed to advance theworking head into the myocardium. The cam surfaces on the working headengage the myocardium tissue to form a bore or channel therein.Preferably, the channel is made approximately one centimeter deep by theadvancement of the instrument with respect to the catheter. This actionis accomplished rather quickly, e.g., in about five seconds. Once thechannel or bore is completed, or during the time of its formation, thefoot control switch 114 is depressed by the operator further to thesecond switch position. This action results in electric power beingprovided via the controller 86 to the injector 50. In particular,electrical power is provided via line 118 to the jack of the controller,whereupon the jack commences inward movement, thereby causing immediatedelivery of the agent(s) 24 into the tubing (the pushing of the ramcauses the capsule to be pierced by the piercing needle 60 whereupon theagent flows through the needle into the communicating tubing 62, throughthe inlet port 106A of the highest wins valve (since this is port willnow be at a higher pressure level than port 106B), whereupon theflowable agent will flow through communicating outlet line 108 into theinterior of the delivery instrument 26 at the proximal end thereof. Theagent is delivered down the delivery instrument to the working headeither by continued motion of the ejector (assuming the capsule chargeis large enough) or is carried forward by the continuing flow of salinefrom the pump 112. It is expected that the delivery of the agent(s) 24from the capsule to the bore within the myocardium be delivered quitequickly, e.g., in five seconds or less.

In accordance with one preferred use of the system of the subjectinvention, e.g., the vascularization of the myocardium, plural bores,lumens or channels are formed in the myocardium by repeating theprocedure as set forth above. As should be appreciated by those skilledin the art, the number of bores or channels, their size (e.g., innerdiameter and depth), their spacing, and the tissue area encompassedthereby will be a matter of choice based on the desires of the operatorof the system and the particular tissue treatment desired. Formyocardial vascularization applications of this invention it iscontemplated that the bores or channels created be within the range of ¼to 3 mm in diameter, extending in depth from 1-20 mm, and being spacedfrom one another by 0.25 cm to 5 cm. The area coverage of cardiac tissueencompassed by the bores or channels may be from 1 to 100 squarecentimeters. Moreover, the size of the particles forming the flowableagent(s) or included in the flowable agent(s) will, of course, be afactor in the determination of the dimensions, spacing and geographicextent of the channels in the targeted tissue.

If it is desired to time the introduction of the delivery system and theflowable agent(s) 24 into the myocardium to any particular portion ofthe patient's cardiac cycle (e.g., during diastole) then the system 20preferably includes a cardiac cycle monitor 121 for providing EKG and BPoutput signals in response to signals provided from associated cardiacsensor(s), e.g., skin-mounted electrodes (not shown) on the patient. Ascan be seen in FIG. 5A the cardiac cycle monitor 121 is arranged toprovide signals, via a line 133, to the controller 86, in response tothe monitored cardiac cycle of the patient. The controller 86, in turn,controls the operation of the injector 50 to the delivery instrument 26in coordination with the sensed cardiac cycle. Thus, the controller 86can be used to initiate operation of the system to deliver the flowabletreatment agent(s) into the myocardium at a predetermined point in thecardiac cycle.

If angiographic placement of the delivery instrument 26 is required, thesystem 20 preferably includes the heretofore identified manifold 102 aswell as associated components, such as a bag of a contrast medium 123, abag of saline 125, and a syringe 127 for delivery of a bolus of thecontrast medium through the guide catheter 28 via the conduit or line100. A blood pressure transducer 131 is also provided connected via aline 129 to the manifold. The transducer 131 provides blood pressuresignals to the monitor 121.

In FIG. 5B there is shown an illustration of a system for deploying theflowable agent(s) 24 into the wall of a coronary blood vessel, such asthe left anterior descending (LAD) artery 11. Thus, the illustration inFIG. 5B is identical to that as shown in FIG. 5A except for thepositioning of the guide catheter 28 and the delivery instrument 26 inthe left anterior descending coronary artery of the heart.

In this application, the delivery instrument 26 is passed through theguide catheter 28 to the LAD where it distributes the flowable agent(s)24 into the wall of the LAD by ejecting the agent(s) at a high velocity.This is accomplished by the combination of pressure and the rotarycentrifugal action of the working head. To that end, the instrument 26is inserted into the guide catheter 28 and moved to a location justinside the guide catheters distal tip under fluoroscope vision. Theoperator of the system then depresses the foot control switch 114 to thefirst position, whereupon nitrogen flows to the turbine 82 which in turnrotates the working head 30 at the distal tip of the instrument. Theoperator then advances the instrument longitudinally by sliding the knob94 in the slot in the cradle until the working head is advanced to theappropriate location in the vessel. The foot switch 114 may then bedepressed in the second position, whereupon the capsule ejector ram 68is driven smartly into the capsule, thereby causing the needle to pierceinto the capsule so that the agent(s) 24 flows through the tubing 62into the input 106A of the highest wins valve 106 and from there throughthe outlet tube into the interior of the instrument 26. The instrumentis then delivered down the instrument to the instrument's working headeither by continued motion of the injector (assuming the capsule chargeis large enough) or is carried forward by the continuing flow of salinefrom the peristaltic pump 112. In any case, the flowable material isforced out in a somewhat radial direction, such as shown by the arrowsin FIG. 5B whereupon it passes through the artery wall and into thecontiguous tissue of the myocardium.

FIG. 6 is an enlarged portion of the illustration shown in FIG. 5B.Thus, it can be seen that when the delivery instrument is located sothat it is within the desired coronary artery, e.g., the left anteriordescending (LAD) artery 11, its distal end portion extends beyond thedistal end of the guide catheter and lies approximately centered withinthe artery and parallel to the longitudinal axis thereof. Operation ofthe instrument 26 causes the tip to bombard the surrounding tissue withthe propelled fluids (e.g., the agent(s) 24 with or without saline orother flowable materials at a high pressure). This action forces theflowable liquids into and through the artery wall and into theimmediately adjacent myocardium tissue. This is achieved by increasingthe local dynamic or hydrostatic pressure induced by the injectedflowable materials and/or the movement, e.g., rotation, of the workinghead. The construction of the instrument allows the flowable agent(s) tobe delivered and dispersed into a significant volume of cardiac tissue.As will be described in considerable detail later, the flowablematerials or agents may be in the form of fine particulates, e.g.,microspheres, which, when dispersed into the cardiac tissue cover arelatively wide area, yet are resistant to further migration, therebyretaining their beneficial effect within the desired portion of theheart.

FIG. 7 is an illustration of a portion of the heart of a living humanbeing, shown partially in section and showing an alternative embodimentof the delivery instrument of the subject invention for introducing theflowable agent(s) 24 therein. In the embodiment shown in FIG. 7, thedelivery instrument is designated by the reference number 200 and is inthe form of a jet injector. The instrument is used to deliver into themyocardium the flowable materials via the epicardium. To that end, theinstrument utilizes a pressurized stream of fluid to distribute theflowable agent(s) into the targeted tissue.

The use of pressurized fluids for medical applications has been knownfor some time for various applications. For example, pressurized fluidshave been used in the past to ablate and remove substances from thebody. See for example U.S. Pat. No. 1,902,481 (Pilgrim). This patentdiscloses the use of a pressurized fluid or medicant to flushundesirable substances from body cavities of animals. U.S. Pat. No.3,930,505 (Wallach) discloses a surgical apparatus for the removal oftissue from the eye of a patient by making use of a low pressure, e.g.,15 to 3500 psi jet, to disintegrate that tissue. Particles, such as saltcrystals, may be introduced into the jet. A suction pump is used formaterial removal. U.S. Pat. No. 4,690,672 (Veltrup) discloses a lowpressure, e.g., less than 450 psi water jet for ablating deposits. Avacuum pump is also used for evacuation of the fragmented material whichis ablated. U.S. Pat. No. 5,496,267 (Drasler) discloses a device for theablation and removal of thrombus deposits from tissue walls of patientsby means of a high pressure jet, e.g., 5,000 to 50,000 Psi. The deviceof that patent may be used to infuse drugs, inject contrast media forvisualization and flush the vessel. U.S. Pat. No. 5,037,432 (Molinari)discloses an apparatus utilizing pressurized fluid in conjunction withan abrasive reducing substance for removing surface portions of humantissue. The device allows a controlled application of a reducingsubstance for the purpose of obtaining a superficial abrasion of surfaceportions of the human tissue. This patent does not contemplate utilizingthe system for a surgical or percutaneous tool, nor the delivery of asubstance into the tissue.

The delivery instrument 200 shown in FIG. 7 is arranged to drive theflowable agent(s) 24 at high pressures into the myocardium and thusimplant the agent(s) at some significant distance from the instrument'sdistal end 202, as indicated by the arrows in this figure. Theinstrument 200 is a generally rigid or partially rigid device for use inopen heart surgery or for use in mini-open heart surgery through athoracotomy. Like the instrument 26 described heretofore, the deliveryinstrument 200 is arranged to drive the flowable agent(s) 24 at highpressures into the myocardium 3 to thereby implant that agent at somesignificant distance from the instrument's distal or working end.However, unlike the delivery instrument 26 (which is threaded throughthe vascular system to a position so that its working head 300 isextended into the ventricle or through a coronary artery to be adjacentthe site into which the flowable material will be introduced into themyocardium), the instrument 200 is arranged to penetrate the myocardiumdirectly from the epicardium to introduce the flowable agent.

As best seen in FIG. 7 the delivery instrument 200 basically consists oftwo main portions, namely, a flowable agent capsule receiving portion202 and an elongated injector tip portion 204. The capsule receiverportion 202 is in the form of an elongated body which is particularlysuited to be grasped in the hand of the user. The body forms theproximal end of the instrument 200. The injector tip portion 204 is anelongated, small diameter, e.g., 1 mm, member which extends from thedistal end of the body portion 202 to thereby form the distal end of theinstrument. The receiver portion 202 is a generally hollow member havinga cavity 206 for receipt of a rupturable capsule, like capsule 72described heretofore. The outlet of the capsule 72 is in communicationwith a passageway 208 in the form of a metal tube of small bore, e.g.,0.015 inch, which extends down through the injector tip 204 to thedistal end 210 thereof. As can be seen, the distal end of the tip ispointed to form a piercing member. A plurality of outlet ports 212 areprovided in the distal tip and are in fluid communication with thepassageway 208. The ports are equidistantly spaced about the peripheryof the tip and are directed radially outward therefrom. The ports arearranged to allow the flowable agent(s) 24 to exit the instrument 200 inthe form of plural, radially outwardly directed, high pressure fluidjets which are shown graphically by the arrows 24 in FIG. 7.

The delivery instrument 200 illustrated in FIG. 7 only shows theflowable agent(s) 24 delivered to the myocardium 3 in one area. However,it should be appreciated that the instrument may be positioned atdifferent levels in the myocardium to deliver the flowable agent(s) intothe entire depth of the myocardium. Further still, the distal portion204 of the instrument 200 may include a plurality of ports 212 atdifferent longitudinal positions therealong to distribute the flowableagent(s) into the myocardium at various levels with a single delivery orpenetration.

In order to propel the flowable agent(s) out of the capsule to formthose jets, the instrument 200 includes a fast acting plunger assembly.In particular, the assembly comprises a plunger 214 located immediatelyproximally of the piston 64 at the proximal end of the capsule 72. Theplunger is located within a bore 216 in the body portion 202. A powerfulspring, not shown, forming a portion of the plunger assembly is locatedproximally of the plunger and is normally held in a retracted, loadedposition by a trigger mechanism, not shown. When the trigger mechanismis actuated by the user, it releases the spring to advance the plungerrapidly through the bore in the distal direction to engage and move thepiston distally. The rapid distal movement of the piston pressurizes theagent 24 within the capsule to cause the capsule wall to burst andthereby enable the flowable agent to flow down the passageway 208 to theports 212 where it exits in plurally radially directed high pressurejets.

It should be pointed out that the delivery instrument 200 can beconstructed in accordance with the teachings of U.S. Pat. No. 2,398,544(Lockhart) or any other prior art injector device using springs or othermechanisms for driving an agent from a capsule or receiver locatedtherein.

In any case, the sizing of the parts of the instrument is preferablyselected so that pressures of several thousand psi can be generated bythe actuating mechanism, e.g., plunger and capsule combination. Suchpressures are more than adequate to drive the flowable agent(s) jets asignificant distance into the penetrated tissue, e.g., the myocardium.

To expedite the vascularization of cardiac tissue, the tip 210 of thedevice 200 is preferably pointed so that it may penetrate into thecardiac tissue a limited distance, e.g., 1-20 mm, such as shown in FIG.7. Once it is at the appropriate depth, the agent 24 may then bepressurized and forced into the tissue through the ports 212 asdescribed earlier. Depending on the application, one or pluralpenetrations can be undertaken.

In some applications, a depth control means (to be described later) maybe provided to limit the depth of penetration of the distal or workingend of the instrument 200 into the myocardium to disperse the flowableagent(s) into the contiguous tissue. Such depth control means maycomprise means to limit the depth of the lumen(s) created by thedelivery instrument, or may comprise means on an insert (to be describedlater) which is implanted into the targeted tissue to limit its depth ofpenetration into the lumen or may be a combination of both. The depthcontrol means of the delivery instrument may be adjustable to vary thedepth of the lumen(s) created by the instrument. The optimal lumen depthcreated by the instrument may be determined before the procedure orduring the procedure by measuring the thickness of the cardiac tissuewith a transesopheageal echocardiogram probe, ultrasound probe, or othermeasuring instrument.

It should be pointed out at this juncture that while the deliveryinstrument 200 is shown making use of a rupturable capsule 72, like thatdescribed heretofore, it should be clear that the instrument can makeuse of other types of capsules, such as the needle-puncturable capsule52 described earlier, for holding the flowable agent(s). In such analternative arrangement, a piercing needle 60, like that describedheretofore, is provided in the injector located proximally of and incommunication with the metal tube 208. The needle is directed towardsthe cavity holding the capsule so that it can pierce the end wall of thecapsule when the capsule is moved into the point of the needle by thedistal movement of the piston 64.

It should also be pointed out at this juncture that the flowable agentcan include a flowable carrier material if desired. The flowable carriermaterial can be arranged to harden slightly after placement, like epoxyor silicon caulking material, so that it is not extruded from thecardiac tissue after penetration during the cardiac contraction cycle.As will be discussed later, a significant feature of the subjectinvention is the stimulation of a foreign body reaction and healingresponse in the myocardium which results in the formation of capillariesat the site of and adjacent the implanted flowable agents.

FIG. 9 is an illustration of the heart of a living human being,partially in section, showing one embodiment of another flowableagent(s) delivery instrument 400 forming a portion of a targeted tissuetreatment, e.g., myocardial revascularization, system of the subjectinvention. In this case, the instrument is a vibratory device which isused to penetrate a portion of the epicardium 2 and then into themyocardium 3 to deliver the flowable agent(s) into the myocardium.Vibratory energy provided by this embodiment may be sonic, ultrasonic orother energy used to create channels or lumens in the targeted tissueinto which the flowable agent(s) 24 will be ejected or deposited fordispersion into tissue contiguous with the lumen or channel into whichit is introduced. Alternatively, the deployment instrument 400 canprovide one or more of various other types of energy to the targetedtissue to create the channels or lumens and then deliver the flowableagents therein. Examples of other types of energy contemplated for suchprocedure are thermal energy, mechanical energy (e.g., rotationalcutting or boring, slicing, etc.), electrical energy (e.g.,radiofrequency energy, etc.), hydraulic energy (e.g., pneumatic energy,radiation energy, laser or other light energy, or other types ofelectromagnetic energy, etc.) It should be pointed out at this juncturethat the application of energy to the cardiac tissue will not only serveto create the lumens or channels but can also disable or denervate localnerves in the targeted tissue. This factor may prove particularlysignificant for cardiac tissue treatment applications by minimizing orotherwise reducing patient-pain resulting from angina.

In some applications, such as where the deployment instrument 400applies electrical energy to the cardiac tissue to form the lumens orwhere the formations of the lumens and/or the deployment of the flowableagents therein is best accomplished during a particular portion of thecardiac cycle, the targeted tissue treatment system utilizing avibratory instrument like instrument 400 may also include some controland sensing means (such as will be described later) that synchronizesthe operation of the delivery instrument to a specific portion of thecardiac cycle.

The instrument 400 as shown herein is merely exemplary. Thus, it can beof any suitable construction. For example, it can be constructedsimilarly to the device disclosed in U.S. Pat. No. 4,315,742 (Sertich)whose disclosure is incorporated by reference herein. That devicebasically comprises an air-powered vibratory instrument which vibratesat approximately 7 KHz. This example is not intended to exclude othermeans for generating vibratory energy for the instrument 400, such asmagnetostrictive or piezoelectric devices. In the exemplary embodiment400 shown herein, the device basically comprises the device of theaforementioned Sertich patent with an alternative tip 402 constructed inaccordance with this invention and as shown in FIG. 10 herein. Inparticular, as can be seen in FIG. 10, the tip 402 is an elongatedangled member which is arranged to be attached to the screw thread atthe distal end of the Sertich device. The angled tip is present within aholder 404. The free end of the tip is rounded at its distal end 406 andincludes plural small radially directed outlet ports 408 fordistribution of the flowable agent(s) 24. The tip may be of a continuoustapered form (not shown) or a step form having a reduced diameter distalsection 410 including the free end 406 as shown in the illustration ofFIG. 10. The fact that the distal end of the tip is of reduced diametercoupled with the fact that it is located a distance from the holder 84serves to amplify the vibration produced by the instrument duringoperation. The flowable agent 24 is provided by the instrument 400, aswill be described later, and exits from the plural ports 408 in the formof plural radially directed outward jets as shown by the arrows in FIG.9.

FIG. 11 shows a complete targeted tissue treatment system 20 making useof the vibratory delivery instrument 400 just described to effect thevascularization of the myocardium. Thus, as can be seen, the free end406 of the tip 402 of the instrument 400 is placed against theepicardium and the foot control switch 114 is depressed to the firstposition. Nitrogen gas passes through the tube 110 directly to theinstrument 400 thus generating vibrations in the tip 402. Concurrently,saline flows from the bag 116 through the pump 112 to the input 106B ofthe highest wins valve 106 and from there through the feed line 108 intothe interior of the instrument 400. The saline flows through theinstrument to the tip and out through the ports 408. This action bores achannel or lumen through the epicardium into the myocardium. When thishas been accomplished, the foot switch is then depressed to the secondposition, whereupon the capsule injector ram 68 of the system 20 isdriven smartly into the capsule 52, thereby ejecting the flowableagent(s) 24 through the highest wins valve port 106A into the feed tube108. The agent(s) 24 is delivered through the instrument 404 to its tip402 either by continued motion of the injector (assuming the capsulecharge is large enough) or carried forward by the continuing flow ofsaline from the pump. The flowable agent thus is driven into themyocardium by the use of pressure alone or by the vibration of theinstrument alone or by a combination of both.

FIG. 12 is an illustration, not to scale, of the heart of a living humanbeing, shown partially in section, and illustrating an embodiment ofanother alternative flowable agent(s) delivery instrument (not to scale)forming a portion of a targeted tissue, e.g., myocardialrevascularization, system of the subject invention. This embodiment isdenoted by the reference number 500 and basically comprises a jetinjector which is used to deliver the flowable agent(s) 24 as apressurized stream into the myocardium 3 via the epicardium 2.

As is known, pressurized fluids have been used in the past in jetinjector devices for administering intramuscular and subcutaneousmedications to a patient through the patient's skin, without the use ofa skin-penetrating needle. The advantages of such systems include thereduction of pain and apprehension associated with needle injections,the elimination of needle-stick injuries, and the reduction ofenvironmental contamination associated with needles. Jet injectiondevices have been considered for immunization vaccines, hormonedelivery, local anesthetics, and insulin delivery. For example, U.S.Pat. No. 2,398,544 (Lockhart) discloses a hypodermic injector foradministering a liquid through the skin of a living being without thenecessity of having a needle puncture the skin. The device uses apressure of 8,000 to 10,000 psi to force a stream of a liquid throughthe skin. U.S. Pat. No. 2,737,946 (Hein) discloses an apparatus forhypodermically injecting medicants through the skin without the use of apenetrating needle. U.S. Pat. No. 2,762,370 (Venditty) discloses aneedleless hypodermic injector for use in discharging liquid medicantsfrom an orificed ampule in the form of a minute stream. An initialhigh-pressure discharge causes the jet stream to distend the skin andforce the liquid to a predetermined depth beneath the surface. After theminute opening in the epidermis has been produced, the pressure of thestream is immediately reduced to a lower second stage for completingtransfer of the remaining liquid from the ampule. U.S. Pat. No.2,800,903 (Smoot) discloses a device for the injection of a medicantwithout the use of a long needle. U.S. Pat. No. 5,704,911 (Parsons)discloses a system utilizing hypodermic jet injections to deliver liquidmedicants without piercing the skin with a needle. U.S. Pat. Nos.4,165,739 (Doherty et al.) and 3,815,514 (Doherty) disclose innoculatorsfor injecting a fluid through the skin without the use of a needle.

Referring now to FIG. 12, it can be seen that the jet injector deliveryinstrument 500 as illustrated is constructed similarly to theinoculation injector described in U.S. Pat. No. 2,398,544 (Lockhart)whose disclosure is incorporated by reference herein. This constructionis referred to since it is illustrative of some forms of devices thatare suitable for the purpose of injecting a flowable agent into atargeted tissue, e.g., the myocardium, under high pressure. Other typesof jet injectors could be utilized in accordance with this invention.

As can be seen clearly in FIG. 12, a capsule 502 containing a flowableagent(s) constructed in accordance with this invention is held within adispensing chamber in a cap portion 504 of the jet injector instrument500. The cap includes multiple tiny orifices 506 arranged in a pattern,e.g., equidistantly spaced and slightly flared outward, to give a widespread to the injected agent(s) 24 within the myocardium. Alternatively,the injector device may only include a single orifice for injecting asingle jet stream of the agent into the myocardium. In the embodimentshown, the instrument 500 includes an activatable plunger 508 which isarranged to be released by axial motion of a sleeve 510 to rapidlyengage or push into the capsule 502. This action propels the flowableagent(s) 24 of the capsule through the orifices 506 in the cap 504 andinto the contiguous cardiac tissue, i.e., through the epicardium andinto the myocardium as shown by the arrows in FIG. 12.

It should be pointed out at this juncture that the instrument 500 may beconstructed differently. For example, the instrument 500 could consistof a local jet holder, like cap 504, but with the pressure source andcapsule remote from the tip.

During the operation of the system of FIG. 12, the agent or carrierfluid for the agent (to be described later) intended for introductioninto the targeted tissue is inserted in a proper dosage into thedispensing chamber. As discussed previously, pre-dosed capsules can beutilized. In any case, the plunger is driven forward by the linearlyapplied force and converts this force into pressure on the flowableagents. The force is sufficient to cause the flowable agents to exit thechamber via the orifice(s) 506 at such a velocity that they can behypodermically injected into the injection site. It is possible that anampule or other agent reservoir could be used and as such the ampulecould utilize a dosage scale or graduations for use in metering properdoses. Moreover, it is conceived, but not illustrated, that anembodiment of a needleless hypodermic injection delivery instrument ofthis invention would include an ampule assembly having a chamber forholding the flowable agent(s), e.g., a liquid suspension, and aninjector for receiving and mounting the ampule assembly. In such a case,the ampule assembly will have an opening at an end of an ampule shellthrough which the flowable agent can be drawn into an ejected out from.A plunger assembly movable within the chamber is used for drawing theflowable agent into the chamber and for injecting the material out ofthe chamber. The injector applies a force that activates a plunger tothereby force the material to leave the chamber via the orifice(s) at avelocity sufficient that the agent can be hypodermically injected intothe targeted tissue. The force may be applied by a firing mechanism thatreleases compressed gas from a storage compartment. The compressed gasacts upon a piston which drives the plunger to subsequently eject thepreselected dosage of the flowable agent(s) through the orifice(s) atthe distal end of the instrument. A shock absorber may be used to softenor cushion the shock of the triggering mechanism. For some flowableagents, e.g., vaccines, there may be a standard implant dosage, whilefor other agents there may be variable size dosages, e.g., weightdependent medications. Safety interlocks, not shown, can be incorporatedto prevent system activation until the delivery instrument is fullysecured in position.

In some applications it may be desirable to stabilize the flowableagent(s) delivery instrument against the targeted tissue, e.g., theendocardium or epicardium during the tissue treatment, e.g.,revascularization, procedure. For such applications, the system 20 maymake use of some releasable securement or attachment means, like thatshown in FIG. 13. That means basically comprises a suction hood, to bedescribed in detail later, which stabilizes or otherwise holds theflowable agent delivery instrument in place. Once positioned, thedelivery instrument can be activated to direct the flowable agent(s)therefrom into the targeted tissue. It must be pointed out at thisjuncture that the use of the stabilization as disclosed herein is notconfined to the use with any particular type of delivery instrument.Thus, it can be used with powered, e.g., rotatable working headinstruments like shown in FIG. 2, or manually driven instruments likeshown in FIGS. 7, 9 and 13, to create lumens within the targeted tissueand to introduce the flowable agent(s) therein. FIG. 13 illustrates onesuch device when applied to the delivery instrument of FIG. 7. Thus,referring now to FIG. 13, there is shown a delivery instrument 200 ofFIG. 7 but including a releasably securable attachment mechanism 600 inthe form of a suction hood 602 assembly and associated components. Thesuction hood assembly is slidably mounted on the distal portion 204 ofthe instrument 200. The suction hood assembly 602 basically comprises acup-shaped hollow member formed of a resilient material, e.g., siliconerubber, having a central passageway 604 therein for accommodating thedistal end portion 204 of the delivery instrument 200 (or any otherdelivery instrument). The periphery of the cup-shaped member is in theform of an enlarged flange which is arranged to directly engage theepicardium or other targeted tissue. A source of vacuum 606 is providedcoupled to the proximal end of a tube 608 in communication with theinterior of the cup-shaped hood. The vacuum source 606 is arranged to beactuated by the operator of the system via any suitable means (notshown). This action couples the vacuum source 606 to the interior 610 ofthe hood to produce suction at the distal end of the hood therebyholding it in place on the targeted tissue, e.g., epicardium, centeredover the location at which the delivery instrument 200 is to enter theunderlying tissue. The operator can then drive the instrument 200inwardly into and through the epicardium and into the myocardium withthe suction cup stabilizing the zone of interest.

FIG. 14 shows the flowable agent(s) delivery device 300 of FIG. 8 butused in a tissue treatment application wherein the distal end portion ofthe instrument is fed through the urethra 14 into the prostate gland 15of a living male being for the purpose of delivering the flowableagent(s) 24 along a flow path formed by tube 208 and exiting by way ofnarrower outlet port(s) 212 into the prostate gland in the form of jetsof that agent. The reduced size of the outlet port(s) relative to thediameter of the flow path creates a higher velocity of the exitingflowable agent than its velocity in the flow path. The instrument 200could thus be used to treat prostate cancer, benign prostatehyperplasia, or other prostate conditions with suitable flowabletreatment agent(s), such as tissue and/or vascular antagonists. Ifdesired, the instrument may be positioned so that its distal end iswithin the bladder 16 to deliver the flowable treatment agent(s) theretofor treating a tumor T.

In accordance with one preferred aspect of this invention, the flowableagent(s) is in the form of a plurality, e.g., a host or myriad, of smallparticles of one or more materials (the materials to be described in thetables to follow) either alone or in combination with some carrierfluid, e.g., a liquid. Preferably, the particles are in the form ofmicrospheres or other microparticles. FIGS. 15A-15H show respectiveembodiments of the microparticles which may be used as the flowableagent or as part of the flowable agent or for delivering flowable agentsinto the tissue of a living being in accordance with this invention.

As described previously, the agents 24 are formed of at least onematerial that can elicit a beneficial response within cardiac or othertissues. For example, the agents can be of a pharmaceutical or geneticnature and their presence can initiate a bio-chemical/biological processthat stimulates the tissue to heal itself. The agents can also triggerthe onset of a foreign body or healing response to cause the formationof lumens in communication with the arterial system.

Before describing the exemplary embodiments of the microspheres shown inFIGS. 15A-15I

The flowable materials may be of any particulate size from approximately1 micron to approximately 1 mm. In FIGS. 15A-15I, the particles areshown as being microspheres or microparticles.

Referring now to FIG. 15A, it can be seen that while there is shown asingle microsphere 700 which along with others can be used to form theflowable agent. The microsphere 700 basically comprises an outer layer702 and an inner core 704. The outer and inner layers may be ofdifferent materials or contain different agents or differentconcentrations of the same agent. By varying the absorption rate of thedifferent layers, the release rate of any agent stored in the materialwill vary accordingly. Additionally, the inner core can be anencapsulated liquid containing an agent or plural agents.

FIG. 15B shows a microsphere 706 having a matrix of small pockets ofagents 708 dispersed therein. As the microsphere 706 is absorbed, theagents in the matrix are released.

FIG. 15C shows a microsphere 710 having a matrix of small pockets ofagents 714 dispersed therein and which matrix is coated by a continuousshell 714. The shell can contain no agent or different agents than arecontained in the interior matrix.

FIG. 15D shows a microsphere 716 having an outer layer 718 and anencapsulated liquid core 719 containing the agent(s).

FIG. 15E shows a microsphere 720 having multiple layers 722 with thincoatings of agents 724 between each layer. As the layers 722 areabsorbed, the agents 724 between the layers will be released.Additionally, the thin layers may comprise a material that may not berelated to the treatment of the targeted tissue; but rather is anintermediate material which connects two layers of material. Forexample, it may comprise a coating applied to a polymer surface thatcontains receptors for a specific biological material, e.g., arecombinant adenovirus expressing human fibroblast growth factor-2(FGF-2).

FIG. 15F shows a homogeneous microsphere 726 that is evenly seeded withagents 728 throughout. The agents 728 are uniformly released as themicrosphere is absorbed.

FIG. 15G shows a microsphere 730 that is coated with a thrombogenicagent 732 such as thrombin, that will promote clotting of blood aroundthe agent to prohibit movement of the agent through the tissue after itis deposited.

FIG. 15H shows a microparticle (not a sphere, but rather an irregularlyshaped body) 734 seeded with a matrix of encapsulated agents 736throughout. The irregular shape of the body 734 tends to render itresistant to movement after it is deposited in the targeted tissue.

FIG. 15I shows a small shard or piece of a polymer 738 or some othermaterial that could be coated or seeded with a suitable treatment agent.The irregular shape of the polymer body also serves to prevent movementof it after it is deposited in the targeted tissue.

As is know, microspheres are well known for their use in long termcontrolled release of drugs or other therapeutic agents. This is ahighly developed technology that has been used in many applications andsuch microspheres are available from a variety of sources (e.g.,Polymicrospheres, Indianapolis, Ind.). The microsphere structurestypically consists of: (a) a continuous drug phase surrounded by acontinuous barrier membrane or shell (microcapsule), (b) a shellstructure where the drug phase is subdivided into numerous domainsscattered uniformly through the interior of the microsphere, (c) apolymer matrix throughout which the drug is uniformly dispersed, (d) astructure where the drug is either dissolve or molecularily dispersedwithin the carrier material from which the microsphere is prepared, and(e) solid. The most common method of delivering drugs or othertherapeutic agents with microspheres incorporates these agents uniformlywithin a polymer matrix.

The fabrication of and application of microspheres is well known and assuch the following examples are included herein as reference. U.S. Pat.No. 3,887,699 describes a solid biodegradable polymer spheroids implantswhich incorporate a drug for sustained release as the polymer naturallydegrades in the human body. Many different methods of constructing thistype of controlled release system have been developed. Although theuniform matrix of a polymer provides a simple and efficient means ofcontrolled release of agents with microspheres, many advanced methods ofcontaining and releasing the therapeutic agents have been developed.U.S. Pat. No. 4,637,905 (Gardner) discloses a method for encapsulating atherapeutic agent within a biodegradable polymer microsphere. U.S. Pat.No. 4,652,441 (Okada et al.) discloses a method of utilizing awater-in-oil emulsion to give prolonged release of a water-soluble drug.The patent describes a wide variety of drugs that can be delivered viaprolonged release micro-capsules as well as suitable polymeric materialsand drug retaining substances. It is conceived that the system of thisinvention could incorporate any of the drugs described to in this patentto generate a beneficial effect in the cardiac tissue. U.S. Pat. No.5,718,921 (Mathiowitz et al.) discloses a method for constructing amultiple layer microsphere which can release two different drugs atcontrolled rates or a singe drug at two different rates. U.S. Pat. No.5,912,017 (Mathiowitz et al.) also discloses a method of forming twolayered microspheres by using an organic solvent or melting twodifferent polymers, combining them with a desired substance and cooling.Microspheres are not limited to just water-soluble therapeutic agents.See, for example, U.S. Pat. No. 5,288,502 (McGinity et al.) whichdiscloses a multi-phase microsphere which is capable of incorporatingwater-soluble and water-insoluble drugs.

Several embodiments of the subject invention utilize the incorporationof therapeutic agents into microparticles or microspheres that degradeover time and release the therapeutic agents. As a non limiting example,microparticles can be used to deliver any type of molecular compound,such as proteins, genetic materials, proteins, peptides, pharmacologicalmaterials, vitamins, sedatives, steroids, hypnotics, antibiotics,chemotherapeutic agents, prostaglandins, and radiopharmaceuticals. Thedelivery system of the present invention is suitable for delivery theabove materials and others including but not limited to proteins,peptides, nucleotides, carbohydrates, simple sugars, steroids,pharmaceuticals, cells, genes, anti-thrombotics, anti-metabolics, growthfactor inhibitor, growth promoters, anticoagulants, antimitotics, andantibiotics, fibrinolytic, anti-inflammatory steroids, and monoclonalantibodies. Examples of deliverable compounds are listed in Table 1 and2.

TABLE 1 Examples of Biological Active Ingredients Growth factors Geneticmaterial Fibroblast Growth Factor (FGF) Adenovirus Bone morphogenicproteins (BMP) Hormones Stem Cells Vascular Endothelial Growth Factor(VEGF) Interlukins Insulin-like Growth Factors (e.g. IGF-I)Platelet-derived Growth Factor (PDGF)

TABLE 2 Examples of Pharmaceutical ingredients ThrombinAnti-inflammatorys Anti-proliferative agents Immunosuppressant agentsGlycosaminoglycans Collagen inhibitors Anticoagulants Anti-bacterialagents Vasodilators Calcium channel blockers ACE inhibitors Betablockers Antiarrhythmics Antiplatelets Thrombolytics

Microspheres can be made of a variety of materials such as polymers,silicone and metals. Biodegradable polymers are ideal for use increating microspheres. There are essentially three classes ofbiodegradable polymers: (1) water-soluble polymers rendered insoluble byhydrolytically unstable cross-linking agents, (2) water-insolublepolymers that become soluble by hydrolysis but retain their molecularbackbone, and (3) water-insoluble polymers that become soluble bybackbone cleavage. Polylactic Acid and Polyglycolic Acid are well knownexamples of resorbable polymers. The release of agents from absorbablemicroparticles is dependent upon diffusion through the microspherepolymer, polymer degradation and the microsphere structure. Althoughmost any biocompatible polymer could be adapted for this invention, thepreferred material would exhibit in vivo degradation. It is well knownthat there can be different mechanisms involved in implant degradationlike hydrolysis, enzyme mediated degradation, and bulk or surfaceerosion. These mechanisms can alone or combined influence the hostresponse by determining the amount and character of the degradationproduct that is released from the implant. The most predominantmechanism of in vivo degradation of synthetic biomedical polymers likepolyesters, polyamides and polyurethanes, is generally considered to behydrolysis, resulting in ester bond scission and chain disruption. Inthe extracellular fluids of the living tissue, the accessability ofwater to the hydrolysable chemical bonds makes hydrophilic polymers(i.e. polymers that take up significant amounts of water) susceptible tohydrolytic cleavage or bulk erosion. Several variables can influence themechanism and kinetics of polymer degradation. Material properties likecrystallinity, molecular weight, additives, polymer surface morphology,and environmental conditions. As such, to the extent that each of thesecharacteristics can be adjusted or modified, the performance of thisinvention can be altered.

Finally, many biodegradable polymers are also used to construct thesemicrospheres such as polylactide, polylactide, copolymers withglycolides, lactides and/or epsilon-caprolactone, polyanhydrides,polyorthoesters, and many others. The polymers of poly (d,l-lactic acid)and poly (d,l-lactic) co-glycolic acid are among the most preferredpolymers used historically for controlled release. However, virtuallyany biodegradable and/or biocompatible material may be used with thepresent invention. A list of example biocompatible materials are shownin Tables 3 and 4.

TABLE 3 Biodegradable Polymer Examples Polyglycolide (PGA) PolylactideCopolymers of glycolide Glycolide/L-lactide copolymers (PGA/PLLA)Glycolide/trimethylene carbonate copolymers (PGA/TMC) Polylactides (PLA)PoIy-L-lactide (PLLA) Poly-DL-lactide (PDLLA) L-lactide/DL-lactidecopolymers Lactide/tetramethylglycolide copolymers Lactide/trimethylenecarbonate copolymers Lactide/σ-valerolactone copolymersLactide/ε-caprolactone copolymers Polydepsipeptides PLA/polyethyleneoxide copolymers Poly-β-hydroxybutyrate (PBA) PHBA/γ-hydroxyvaleratecopolymers (PHBA/HVA) Poly-β- hydroxypropionate (PHPA) Poly-p-dioxanone(PDS) Poly-σ-valerolactone Poly-ε-caprolactone Methylmethacrylate-N-vinyl pyrrolidone copolymers Polyesteramides Polyestersof oxalic acid Polydihydropyrans Polyalkyl-2-cyanoacrylatesPolyurethanes (PU) Polyvinyl alcohol (PVA) Polypeptides Poly-β-malicacid (PMLA) Poly-β-alkanoic acids Trimethylene carbonate PolyanhydridesPolyorthoesters Polyphosphazenes Poly (trimethylene carbonates)PLA-polyethylene oxide (PELA) Tyrosine based polymers

TABLE 4 Examples of other suitable materials Alginate Calcium CalciumPhosphate Ceramics Cyanoacrylate Collagen Dacron Elastin Fibrin GelatinGlass Gold Hydrogels Hydroxy apatite Hydroxyethyl methacrylateHyaluronic Acid Liposomes Nitinol Oxidized regenerated cellulosePhosphate glasses Polyethylene glycol Polyester PolysaccharidesPolyvinyl alcohol Platelets, blood cells Radiopaque Salts Silicone SilkSteel (e.g. Stainless Steel) Synthetic polymers Thrombin Titanium

It must be pointed out at this juncture that the agents of thisinvention are preferably configured such that their presence in themyocardial tissue does not significantly limit the contractility of thecardiac muscle. As previously described, the agents may be coated withor contain growth factors, anti-oxidants, seeded cells, or otherdrug/biologically active components depending upon the result desired.

The main feature of these constructions is to stimulate a foreign bodyreaction and a healing response which results in the formation ofcapillaries at the site of the implant. Moreover, the angiogenesisaction resulting by the location of the agents within the lumens overtime will further revascularize the myocardium. As such, these implantsmay provide less of a short term improvement to vascularization, butinstead will lead to a long term improvement.

As should be appreciated from the foregoing whether the system 20 makesuse of non-resorbable or resorbable agents is of little relevance fromthe standpoint of increased blood flow to the myocardium tissue andcapillaries contiguous with the lumens so long as the agents areconstructed suitably.

FIG. 16 is an illustration of a portion of the heart of a living humanbeing, partially in section, showing the embodiment of a jet injectordelivery instrument 200 (described earlier and shown in FIG. 7) shownused to deliver the flowable agent(s) of this invention into themyocardium 3 via the epicardium 2. The coronary vessels 17 perfusing themyocardium are at least partially obstructed by atherosclerotic material18. As previously described, the device 200 utilizes a pressurizedstream to distribute the flowable agents into targeted tissues. In thisparticular embodiment, microparticles or microspheres like thosedescribed earlier and shown in FIG. 15 are implanted or injected into aportion of myocardium in the form of a micro dispersion. The velocity ofthe microparticles when exiting the instrument may be of sufficientvelocity to penetrate the myocardium but not penetrate a coronary vesselif encountered. As previously discussed the instrument 200 may bestabilized on the surface of the heart and the depth of the instrumentin the myocardium may also be controlled. One embodiment of astabilizing and depth control member 800 is shown as part of theinstrument 200.

Referring to FIG. 17, after the instrument 200 shown in FIG. 16 isremoved, the microdistribution of microparticles 24 remain in themyocardium 3. The microparticles 24 are sufficiently implanted into themyocardium to resist movement. The combination of the microparticles andthe injury created by the instrument 200 to deploy and disperse theparticles may effect angiogenesis. Additionally a channel or lumen 19remains in the myocardium area where the instrument was inserted. Aninsert or plug 802 may be placed in the channel 19 after the instrument200 is removed. This action may assist in achieving hemostasis of thepuncture. For this purpose, the insert or plug 802 may be formed of ahemostatic material, such as collagen or alginate, and may incorporatethrombogenic material, such as thrombin, to accelerate hemostasis of thechannel. The insert or plug 802 may also have an enlarged proximal headportion 804 that may limit the depth of insertion depth of the insert orplug and may also serve to stabilize the insert or plug against thesurface of the myocardium. The insert or plug 802 may also be formed ofa material which will contribute to the improved revascularization suchas those listed on Tables 3 and 4. The insert may also serve to maintainthe patency of the channel or lumen. As such, a portion of the insert orplug can be perforated or include channels (see for example the insertsof the aforementioned copending application Ser. No. 08/958,788). Theinsert itself may also act to treat the surrounding tissue. For example,the insert or plug 802 may also comprise a biologically activeingredient or pharmaceutical ingredient as listed on Tables 1 and 2.Finally, the insert or plug 802 may also be useful in the selectiveablation or improvement of electrical conduction pathways, or theselective ablation or improvement of the nerves of the tissue.

FIG. 18 shows the condition of the myocardium 3 after angiogenesis hasoccurred to create significant new vasculature, e.g., capillaries C. Ascan be seen at this time, the microparticles 24 and the insert 802 havebeen absorbed and the channel 19 formed by the instrument have healed.In addition and quite significantly, the microparticles, the insert, andany biologically active materials or pharmaceutical agents which mayhave also been implanted have induced the growth of the new vasculature(capillaries) C or otherwise improved the tissue.

FIG. 19 is an illustration of a portion of the heart 1 of a livingbeing, shown partially in section and showing the embodiment of thedelivery instrument 200 of FIG. 7 used to deliver the flowable agent(s)24 into the myocardium in the form of pressurized streams of fluid. Inthis figure three instruments 200 are illustrated for introducing theflowable agents into the myocardium at three different locations 902,904, and 906. While three delivery instruments 200 are illustratedextending into the myocardium together, the system 20 will typicallyonly include a single delivery for delivering the agents to one site902, 904 and 906 in the myocardium at a time. Therefore, it should beunderstood that FIG. 19 should be understood to depict the sequentialdelivery of the flowable agent(s) 24 into the myocardium 3 by a singledelivery instrument 200.

At high pressures, the stream of flowable agent(s) 24 delivered to themyocardium may cause separation of the myocardial muscular fibers andmay form a channel in the myocardium. If the delivery instrument isinserted into the myocardium at several locations at controlleddistances between insertion points, the channels formed by thepressurized stream of fluid may be contiguous with one another, thusforming a long channel within the myocardium. Furthermore, a portion ofthe myocardium may be normally perfused with blood and an adjacentportion of the myocardium may be ischemic. If the instrument 200 isinserted in a plurality of locations at controlled distances betweeninsertion points in the normally perfused myocardium and extending intoand possibly through the ischemic myocardium, an intramyocardial channel(like that designated by reference number 908 in FIG. 20) from thenormally perfused myocardium extending into the ischemic myocardiumresults. This channel is expected to remain patent, thereby resulting inimmediate increased perfusion to the ischemic myocardium.

Regardless of the immediate patency of the channel 908, the combinationof the mechanical injury produced by the creation of the channel and theflowable agents 24 may cause the creation of additional vasculatureincluding and in addition to the formed channel, thereby resulting inincreased perfusion of the portion of ischemic myocardium. Depending onthe degree of ischemia and the area of ischemic myocardium, severalchannels may be formed in the area of the ischemic myocardium. Thechannels may or may not originate or terminate in a portion of normallyperfused myocardium.

Regarding the pressurized stream of fluid used to create the channel908, the instrument 200 may utilize multiple flowable agents 24 tocreate the channel and implant agents into the myocardium. For example,one flowable agent, e.g., saline mixed with contract medium, may be usedto create the channel and a second flowable agent, e.g., saline withbFGF coated microspheres and VEGF coated microspheres, may be implantedinto the channel and at some significant distance into the myocardiumsurrounding the created channel. Additionally, the channel may be formedin communication with an existing coronary vessel to provide significantblood flow to the channel. The communication of existing vessel andchannel may be effected by creating an opening in the existing vesselwith the delivery of flowable agent in a pressurized stream from withinthe myocardium or from within the vessel.

FIG. 20 is an illustration of a portion of the heart shown in FIG. 19,but after its treatment by the system of the subject invention. Thus, ascan be seen, the channel 908 in the myocardium which was created by thedelivery system of the subject invention is open and may extend betweennormally perfused myocardium and ischemic myocardium to provideimmediate blood flow to the ischemic myocardium. In addition oralternatively the channel 908 may serve as a means whereby new bloodvessels may grow, supplemented by the introduction of a flowable agentas previously described.

In order to prevent the flow of blood from the channel 908 through theinstrument's entry sites 902, 904 and 906 into the myocardium, ahemostatic insert may be applied in each channel created by theinstrument, like that described with reference to FIG. 17.Alternatively, an adhesive material, e.g., fibrin glue, may be appliedto the surface of the myocardium at the delivery instrument insertionpoint or within the channel created by the instrument, to cause theoriginal entry channels close down as shown in FIG. 20.

FIG. 21 is an enlarged sectional view of the distal end portion of thetreatment agent delivery instrument 1000 forming a portion of the tissuetreatment system 20 of this invention. The delivery instrument 1000incorporates an energy applicator, e.g., a laser (not shown), to provideenergy denoted by the arrows designated by the reference numbers 1004into the targeted tissue, e.g., the myocardium 3, to produce a channeltherein and into which the flowable agent(s) 24 may be introduced. Inparticular, the laser beam 1004 from the laser is carried down theinstrument 1000 via any suitable laser energy conductor, e.g., a lightpipe or fiber optic cable 1006. An annular passageway 1008 is providedwithin the distal end portion of the instrument 1000 surrounding thelaser energy conductor 1006. A plurality of exit ports 1010 are locatedat peripherally spaced locations at the distal end of the instrumentadjacent the free end at which the laser energy conductor 1006terminates and are in fluid communication with the passageway 1008. Thepassageway 1008 and the communicating ports 1010 serve as the means toenable the flowable agent(s) 24 to exit from the instrument in pluraljets.

The instrument 1000 of FIG. 21 is inserted into the targeted tissue,e.g., the myocardium, by applying laser energy from the laser sourcethrough the conductor 1006 so that the laser beam 1004 penetrates intothe tissue to form a channel into which the distal end of the instrument1000 may be inserted. Once the instrument 1000 is within the channel inthe tissue, the flowable agent(s) 24 may be introduced into the tissueby causing it to flow down the annular passageway 1008 and out throughthe ports 1010 in the form of pressurized jets. The combination of theapplication of the energy to create the channel plus the delivery of theflowable agent(s) 24 into the tissue contiguous with the channel isexpected to result in increased beneficial effects to that tissue, suchas the formation of new vasculature, denervation, and ablation ofelectrical conduction pathways.

In FIG. 22, there is shown an alternative embodiment of a laser-energybased delivery instrument 1020. In this embodiment, the distal end ofthe instrument 1020 includes an annular laser energy conductor 22 forcarrying the laser energy or beam 1004 down it from the laser energysource (not shown) so that the laser beam exits the instrument in asomewhat coaxial direction as shown. A central passageway 1024 isprovided in the instrument located within the central opening in theannular laser conductor 1022. The passageway 1024 terminates at itsdistal end in a wall having plural outlet ports 1026. The ports 1026 aredirected in a longitudinal or axial direction with respect to theinstrument. It is through these ports 1026 that the flowable agent(s) 24is ejected from the instrument 1020 in the form of pressurized jets asshown in FIG. 22.

It should be pointed out at this juncture that the instrument in FIGS.21 and 22 can utilize RF energy or other electromagnetic energy toproduce the channels in the targeted tissue in lieu of the laser beamdescribed. In any case with the embodiment 1000 shown in FIG. 21, theflowable agent is ejected in a radial direction, whereas with theembodiment of 1020 of FIG. 22, the flowable agents are ejected in anaxial direction.

It should also be pointed out that the tissue treatment systems of thisinvention may be used without the inclusion of particles in the flowableagent. In such a case a fluid, e.g., a liquid or gas, fluid withoutparticles but which may contain one or more of biologically active orpharmaceutical agents, such as but not limited to the agents disclosedin Tables 1 and 2 is delivered into the targeted tissue. Furthermore,the system described herein for the treatment of cardiac tissue may alsobe used in other tissues in the body to effect similar beneficialtreatment. For example, constriction of peripheral arteries oftencreates areas of ischemic tissue not unlike ischemic myocardium as aresult of coronary artery disease. The system of this invention may beused in these or other tissues to deliver therapeutic agents to improveblood flow through the creation of new vasculature. Other beneficialeffects on the targeted tissue which may be achieved by the subjectinvention are pain reduction resulting from denervation in the treatedtissue and interruption of electrical conduction pathways in the treatedtissue resulting from ablation or some other process.

Without further elaboration the foregoing will so fully illustrate ourinvention that others may, by applying current or future knowledge,adopt the same for use under various conditions of service.

1. A tissue treatment system to beneficially treat target tissue withina living being, wherein said target tissue is distant from an entrysitus in non-target tissue, said system comprising a delivery system anda first flowable agent, wherein at least a distal end of said deliverysystem is arranged to be introduced into an interior lumen of the bodyof a living being and to supply kinetic energy and pressure to saidfirst flowable agent to introduce said first flowable agent at an entrysitus comprising a wall defining said lumen, wherein at least a portionof said first flowable agent is delivered non-systemically, with suchenergy and pressure additionally causing said first flowable agent topenetrate said non-target tissue without any mechanical means carryingsaid first flowable agent through said non-target tissue, whereinfurther said first flowable agent comprises at least one of saline,pharmaceuticals, growth factors, biomaterials, genetic based material orcellular based material, and wherein said pressure comprises a highpressure of at least several thousand psi, whereupon said first flowableagent enters said target tissue located beyond said wall of said lumen.2. The system of claim 1 wherein said first flowable agent additionallycomprises small particles.
 3. The system of claim 2 wherein said smallparticles comprise microspheres.
 4. The system of claim 3 wherein saidmicrospheres comprise at least one of resorbable materials,non-resorbable materials or partially resorbable materials.
 5. Thesystem of claim 4 wherein said microspheres are arranged for time-phaseddelivery of said beneficial treatment.
 6. The system of claim 2 whereinsaid first flowable agent additionally comprises a carrier.
 7. Thesystem of claim 6 wherein said carrier comprises a fluid or a gel.
 8. Atissue treatment system to beneficially treat target tissue within aliving being, wherein said target tissue is distant from an entry situsin non-target tissue, said system comprising a delivery system and afirst flowable agent, wherein at least a distal end of said deliverysystem is arranged to be introduced into an interior lumen of the bodyof a living being and to supply kinetic energy and pressure to saidfirst flowable agent to introduce said first flowable agent at an entrysitus comprising a wall defining said lumen, wherein at least a portionof said first flowable agent is delivered non-systemically, with suchenergy and pressure additionally causing said first flowable agent topenetrate said non-target tissue without any mechanical means carryingsaid first flowable agent through said non-target tissue, wherein saidpressure comprises a high pressure of at least several thousand psi,whereupon said first flowable agent enters said target tissue locatedbeyond said wall of said lumen, wherein said kinetic energy enables saidfirst flowable agent to create a channel at said entry situs tofacilitate said penetration, and wherein said system additionallycomprises a second flowable agent.
 9. The system of claim 8 wherein saidsecond flowable agent is delivered systemically.
 10. The system of claim8 wherein said second flowable agent comprises at least one of saline,pharmaceuticals, growth factors, biomaterials, genetic based material,cellular based material, or other beneficial agent.
 11. The system ofclaim 10 wherein said second flowable agent additionally comprises smallparticles.
 12. The system of claim 11 wherein said small particlescomprise microspheres.
 13. The system of claim 12 wherein saidmicrospheres comprise at least one of resorbable materials,non-resorbable materials or partially resorbable materials.
 14. Thesystem of claim 11 wherein said second flowable agent additionallycomprises a carrier.
 15. A tissue treatment system to beneficially treattarget tissue within a living being, wherein said target tissue isdistant from an entry situs in non-target tissue, said system comprisinga delivery system and a first flowable agent, wherein at least a distalend of said delivery system is arranged to be introduced into aninterior lumen within the body of a living being and to supply kineticenergy and pressure to said first flowable agent to introduce said firstflowable agent at an entry situs comprising a wall defining said lumen,wherein at least a portion of said first flowable agent is deliverednon-systemically, with such energy and pressure additionally causingsaid first flowable agent to penetrate said non-target tissue withoutany mechanical means carrying said first flowable agent through saidnon-target tissue, wherein said pressure comprises a high pressure of atleast several thousand psi, whereupon said first flowable agent enterssaid target tissue located beyond said wall of said lumen, and whereinsaid delivery system is arranged to be operated at an approximate centerof a lumen through which said system is introduced.
 16. A system fordelivering a flowable agent to target tissue, comprising: a reservoircontaining a flowable agent therein, the reservoir arranged to generatea high pressure sufficient to cause said flowable agent to enter targettissue; and a delivery instrument including an elongate shaft having aproximal end, a distal end and a flow path therethrough, the proximalend of the shaft connected to the reservoir, the flow path in fluidcommunication with the flowable agent contained in the reservoir, thedistal end of the shaft including an outlet port in fluid communicationwith the flow path such that fluid from the reservoir may be deliveredto the target tissue via the flow path and the outlet port at asufficiently high pressure and exit velocity to at least partiallypenetrate the target tissue, without any mechanical means carrying saidfluid, wherein said sufficiently high pressure comprises a pressure ofat least several thousand psi, and further wherein at least said distalend of said delivery instrument is arranged to be inserted into a livingbeing through an interior lumen of said living being; further whereinsaid fluid accesses said target tissue by traversing tissue making up awall defining said lumen, and wherein said delivery instrument isarranged to be operated at an approximate center of a lumen throughwhich said delivery instrument is introduced.
 17. A system fordelivering a flowable agent to target tissue, comprising: a reservoircontaining a flowable agent therein, the reservoir arranged to generatea high pressure sufficient to cause said flowable agent to enter targettissue; and a delivery instrument including an elongate shaft having aproximal end, a distal end and a flow path therethrough, the proximalend of the shaft connected to the reservoir, the flow path in fluidcommunication with the flowable agent contained in the reservoir, thedistal end of the shaft including an outlet port in fluid communicationwith the flow path such that fluid from the reservoir may be deliveredto the target tissue via the flow path and the outlet port at asufficiently high pressure and exit velocity to at least partiallypenetrate the target tissue, without any mechanical means carrying saidfluid, wherein said sufficiently high pressure comprises a pressure ofat least several thousand psi, and wherein at least said distal end ofsaid delivery instrument is arranged to be inserted into a living beingthrough an interior lumen of said living being, further wherein saidfluid accesses said target tissue by traversing tissue making up a walldefining said lumen, and wherein said flowable agent further comprises acarrier comprising at least one of a liquid and a gel.
 18. A tissuetreatment system to beneficially treat target tissue within a livingbeing, wherein said target tissue is distant front an entry situs innon-target tissue, said system comprising a delivery system and a firstflowable agent, wherein at least a distal end of said delivery system isarranged to be introduced into an interior lumen of the body of a livingbeing and to supply kinetic energy and pressure to said first flowableagent to introduce said first flowable agent at an entry situscomprising a wall defining said lumen, wherein at least a portion ofsaid first flowable agent is delivered non-systemically, with suchenergy and pressure additionally causing said first flowable agent topenetrate said non-target tissue without any mechanical means carryingsaid first flowable agent through said non-target tissue, wherein saidpressure comprises a high pressure, whereupon said first flowable agententers said target tissue located beyond said wall of said lumen, andwherein said high pressure comprises a pressure of at least severalthousand psi.
 19. The system of claim 17, wherein the flowable agent isdistributed into said target tissue.
 20. The tissue treatment system ofclaim 18, wherein said flowable agent is dispersed into said targettissue.